Report
Alterations of Hippocampal Place Cells in Foraging Rats Facing a ‘‘Predatory’’ Threat Highlights
Authors
d
A ‘‘predatory’’ robot altered place cell stability and theta rhythm in foraging rats
Eun Joo Kim, Mijeong Park, ..., Jeiwon Cho, Jeansok J. Kim
d
Spatial correlations decreased as a function of distance from the safe nest
Correspondence
d
Amygdala lesions abolished the predatory robot effects on place cells
[email protected] (J.C.), [email protected] (J.J.K.)
In Brief While fear guides behaviors that help animals minimize exposures to threats in their habitat, the neural basis for discerning safe versus dangerous areas remains unknown. Using an ‘‘ethological’’ paradigm, Kim et al. show that hippocampal place cells exhibit a distance-gradient of danger in rats foraging for food when frightened by a predatory robot.
Kim et al., 2015, Current Biology 25, 1362–1367 May 18, 2015 ª2015 Elsevier Ltd All rights reserved http://dx.doi.org/10.1016/j.cub.2015.03.048
Current Biology
Report Alterations of Hippocampal Place Cells in Foraging Rats Facing a ‘‘Predatory’’ Threat Eun Joo Kim,1,5 Mijeong Park,3,4,5 Mi-Seon Kong,1 Sang Geon Park,3 Jeiwon Cho,3,4,* and Jeansok J. Kim1,2,* 1Department
of Psychology in Neuroscience University of Washington, 3921 West Stevens Way Northeast, Seattle, WA 98195-1525, USA 3Center for Neural Science, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 136-791, Korea 4Neuroscience Program, Korea University of Science and Technology, 217 Gajeong-ro, Daejeon 305-701, Korea 5Co-first author *Correspondence: [email protected] (J.C.), [email protected] (J.J.K.) http://dx.doi.org/10.1016/j.cub.2015.03.048 2Program
SUMMARY
Fear is an adaptive mechanism evolved to influence the primal decisions of foragers in ‘‘approach resource-avoid predator’’ conflicts [1–3]. To survive and reproduce, animals must attain the basic needs (food, water, shelter, and mate) while avoiding the ultimate cost of predation [4]. Consistent with this view, ecological studies have found that predatory threats cause animals to limit foraging to fewer places in their habitat and/or to restricted times [5–7]. However, the neurophysiological basis through which animals alter their foraging boundaries when confronted with danger remains largely unknown. Here, we investigated place cells in the hippocampus, implicated in processing spatial information and memory [8–10], in male Long-Evans rats foraging for food under risky situations that would be common in nature. Specifically, place cells from dorsal cornu ammonis field 1 (CA1) were recorded while rats searched for food in a semi-naturalistic apparatus (consisting of a nest and a relatively large open area) before, during, and after encountering a ‘‘predatory’’ robot situated remotely from the nest [11]. The looming robot induced remapping of place fields and increased the theta rhythm as the animals advanced toward the vicinity of threat, but not when they were around the safety of the nest. These neurophysiological effects on the hippocampus were prevented by lesioning of the amygdala. Based on these findings, we suggest that the amygdalar signaling of fear influences the stability of hippocampal place cells as a function of threat distance in rats foraging for food. RESULTS Hunger-motivated rats, implanted with tetrode arrays in the cornu ammonis field 1 (CA1) layer [12], underwent successive stages of nest habituation, foraging baseline, and robot testing
stages (Figures 1A and 1B; Supplemental Experimental Procedures). During the baseline, rats were repetitively allowed to leave the nest to procure a food pellet placed at a fixed location in the foraging area. Initially, rats spent considerable time exploring the novel foraging area before discovering the sizeable (0.5/1.0 g) pellet and instinctively bringing it back to the nest for consumption. Afterward, rats ran straight to the pellet and promptly brought it back to the nest, disregarding the area beyond the pellet location. Tetrodes were gradually advanced until complex spike cells were encountered (Figures 1C and 1D) and displayed consistent firing in the nest and/or in the foraging area. The robot testing consisted of ‘‘pre-robot,’’ ‘‘robot,’’ and ‘‘post-robot’’ recording sessions (five to ten foraging trials/session). From ten rats, a total of 78 place cells were recorded. They were classified into three types based on the region of maximal firing: inside the nest (‘‘nest cells’’), near the nest (‘‘proximal cells’’), and distant from the nest (‘‘distal cells’’) (Figure 2A). We found that place cells almost always fired during all three recording sessions, despite the animals’ inabilities to procure the pellet during the robot trials (Figure 2A; Table S1). When place cells were analyzed by performance of a pixel-by-pixel correlation of the maps from pre-robot versus post-robot and robot versus post-robot sessions (with matched foraging distances), all three regions of maximal firing did not differ in the correlation of the firing-rate maps (Figure 2B; F(2, 77) < 0.9, p > 0.4). Comparison between the firing-rate maps from the pre-robot and robot sessions, however, revealed a robot-induced remapping of place fields in the distal region (nearer to the threat), but not in the proximal and nest regions (farther from the threat; Figure 2B; F(2, 77) = 4.175, p < 0.05). Specifically, the pixel-by-pixel correlations of the distal cells were significantly reduced across the pre-robot versus robot sessions compared to the nest cells (p < 0.05), indicating that place cells altered their location-specific firing selective to the threat distance. This is corroborated by the relationship between the x position of the peak and spatial correlation (x position versus z0 pre versus robot, r = 0.265, p < 0.05; x position versus z0 robot versus post, r = 0.044, p = 0.705; x position versus z0 pre versus post, r = 0.033, p = 0.775; Figure 2C). Similarly, the peak distance of the firing-rate maps between the pre-robot and robot sessions was higher in the distal cells compared to the nest and proximal cells (p < 0.01; Figure S1A). Also, in response to the robot, the peak x positions of the distal cells
1362 Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved
Figure 1. Predatory Robot and Place Cells (A) A photograph of a rat in the foraging apparatus. (B) Illustrations of the experimental design. (C) A photomicrograph of tetrodes implants in the CA1 area (arrowhead). (D) Representative waveforms of place cells.
significantly shifted toward the nest direction, whereas the nest and proximal cells showed no reliable directional bias (Figure S1B). The predatory robot also differentially affected the hip-
pocampal theta rhythm, which is implicated in selective attention, arousal, and decision making [13], in a distance-dependent manner. The power spectral density of theta frequency (6–10 Hz; cf. [14–16]) from hippocampal place cells (Figure 3A) revealed that the theta power increased during the robot session compared to the pre-robot session only in the distal cells (p = 0.029; Figure 3B). These distance-dependent differences in place fields and theta power cannot be accounted solely by the change in the animals’ running speed between no-robot and robot sessions because the overall running speeds in distal and proximal foraging areas during the robot session were not different (Table S1). Also, the running speed correlated with neither the firing rate nor the theta power (Table S2). The directionality of the movement was taken into account by subdividing the movement speed as the animal left the nest toward the food (i.e., proximaloutward speed and distal-outward speed) and fled to the nest (i.e., distal-inward speed and proximal-inward speed; R4 pixel bins). Overall, the outward movement was slower than inward movement (robotout, 23.2 ± 2.01; robotin, 37.6 ± 4.33; paired t = 4.27, p < 0.001). However, the movement speeds in both directions were not correlated with the average firing rate (outward speed versus firing rate, r = 0.096, p = 0.557; inward speed versus firing rate, r = 0.151, p = 0.351). To clarify the relationship between the speed change or acceleration and place cells remapping between pre-robot and robot sessions, we calculated the relative running speed [the amount of speed change; (speedrobot speedpre) / speedpre] for each direction (inward and outward). The outward speed change did not differ from the inward speed change between the pre-robot and robot sessions
Figure 2. Distance to the Robot Affects the Stability of Place Cells (A) Example place fields from nest, proximal, and distal cells during pre-robot, robot, and post-robot sessions. The color scale (red, maximal firing; blue, no spike) corresponds to the firing rate for each unit. The numerical value represents the peak firing rate for each session. (B) Differences in the z0 value between sessions inside the nest, proximal to the nest, and distal to the nest. Data are represented as mean ± SEM. *p < 0.05, Bonferroni comparison. (C) Scatter plots showing x positions of peak firing during the pre-robot session versus the spatial correlations (z0 ) between sessions. See also Figures S1, S2, and S4 and Tables S1 and S2.
Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved 1363
Figure 3. Distance to the Robot Affects the Theta Rhythm of Place Cells (A) The population-averaged power spectrum of the nest, proximal, and distal cells. (B) Differences in the theta band (6–10 Hz; gray sections in A) across the pre-robot (dark gray), robot (orange), and post-robot (cyan) sessions. Data are represented as mean ± SEM. *p < 0.05, Bonferroni comparison.
(paired t = 1.48, p = 0.15; Figure S2A). When the speed change was compared between the proximal and distal regions, the relative proximal-outward speed was significantly lower than the relative distal-outward speed (independent t = 5.64, p < 0.001; Figure S2B), and the relative distal-inward speed was not significantly higher than the relative proximal-inward speed (independent t = 1.80, p = 0.083). However, the spatial correlation (z0 ) was related to neither the relative inward nor outward speed (inward relative speed versus z0 , r = 0.030, p = 0.853; outward relative speed versus z0 , r = 0.25; p = 0.125; Figure S2C). Even when the correlational analyses were limited to the distal location data, which showed the biggest behavioral changes between pre-robot and robot sessions, there were no significant influences of movement difference (the amount of speed change) on the spatial correlation of distal cells for outward direction in the distal location (outward relative speed versus z0 , r = 0.282, p = 0.138) or on the average firing rate (outward relative speed versus firing rate, r = 0.087, p = 0.652). In addition, both the inward and outward movement speeds were not correlated with the theta power during the robot session (inward speed versus theta power, r = 0.067, p = 0.680; outward speed versus theta power, r = 0.065, p = 0.689; Figure S2D). Altogether, these results parallel the behavioral finding [11] that normal rats often failed to procure pellets placed beyond 25 cm from the nest, which approximates the nest-to-proximal zone of the present study. Previous studies have shown that amygdalar lesions and inactivations abolished the foraging rats’ fear of the looming robot [11], whereas amygdalar stimulation evoked the same fleeing response in naive rats in absence of the robot [17]. To test whether the robot-induced instability of place fields around the source of threat is mediated via the amygdala-fear system, we recorded place cells in amygdala-lesioned rats (n = 4; Table S3). These rats easily obtained the pellets despite the surging robot (Figure S3A), and the pixel-by-pixel correlation analysis showed that place fields in the distal area remained stable across all recording sessions (Figure 4A) and were comparable to the nest and proximal place fields (F < 2.19, p > 0.12; Figures 4B and S3B). Similarly, there was no difference between the cell types
in the peak distance across sessions (c2 < 1.778, p > 0.411; Figure S3C). No reliable correlation was observed between the peak x position during the pre-robot session and the spatial correlation across sessions (r < 0.213, p > 0.08; Figures 4C and S3D). In addition, the theta power of distal cells in amygdala-lesioned rats (Figure 4D) did not differ across sessions (F(2, 22) = 0.279, p = 0.759; Figure 4E). Although the success rate of procuring food was significantly lower in amygdala-intact rats (14.3% ± 4.13%; mean ± SEM) compared to amygdala-lesioned rats (97.9% ± 1.57%), there were times when few intact rats managed to get the pellet during the robot test (Figure S3A). These data, when analyzed separately, revealed that both the difference in place field stability between distal versus proximal and nest (F < 0.799, p > 0.459) and the correlation between x positions and spatial correlations (z0 pre versus robot, r = 0.146, p = 0.424) were no longer significant (Figures S4A and S4B). Hence, the robot effects on distal place cells emerged when animals were unable to procure the pellet (high state of fear), but not in cases where animals were able to attain the pellet (lower state of fear). DISCUSSION In the present study, the dynamics of hippocampal place cell spikes were recorded under an ecologically relevant ‘‘approach food-avoid predator’’ setting in which the adaptive functions of fear most likely evolved [1, 2, 18]. Under this condition, we found that while place fields were stable inside and nearby the nest (loci of no/low fear), place cells showed instable firing fields at locations neighboring the threat area (locus of high fear). Likewise, the theta rhythm (6–10 Hz) in the hippocampus, which is associated with various behaviors [13], was selectively increased near the vicinity of the robot. These observations suggest a possible scaling relationship between the magnitude of fear, which varies in a relation to the nest-foraging distance, and the stability of hippocampal place fields. Although the looming robot-evoked fleeing responses (effects blocked by amygdalar lesions) suggest fear as the cause of distal place cell instability, an alternative explanation for the finding is the local cue (salience and/or novelty) aspect of the robot signaled by the amygdala. For example, the introduction (or displacement) of a local cue in the environment has been shown to alter a subset of hippocampal place fields ([19–21]; but see [22–24]). In these studies, animals came in physical contact with (and sniffed [21]) the cue or the location where the cue is
1364 Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved
Figure 4. Amygdalar Lesions Abolished the Predatory Robot Effects on Distal Place Cell Stability and Theta Power (A) Distal cells recorded from the amygdala-lesioned rats during pre-robot, robot, and post-robot sessions. The numerical value represents the peak firing rate for each session. (B) Comparisons of the z0 value between the pre-robot and robot sessions in nest (green), proximal nest (purple), and distal nest (red) areas. Data are represented as mean ± SEM. (C) A scatter plot showing x positions of peak firing during the pre-robot session versus the spatial correlations (z0 ) between the pre-robot and robot sessions. (D) The population-averaged power spectrums of nest, proximal, and distal cells in the amygdala-lesioned rats. (E) Comparisons of the theta band (6–10 Hz; gray sections in A) across the pre-robot (dark gray), robot (orange), and post-robot (cyan) sessions. Data are represented as mean ± SEM. See also Figure S3 and Table S3.
no longer present. In contrast, rats in the present study never came close to the remotely placed robot because the robot’s surging motion mainly caused rats to flee into the nest. The possibility of the amygdala’s role in salience and/or novelty [25, 26] influencing hippocampal place fields cannot be excluded, but several studies have shown that amygdala-lesioned rats spent comparable time exploring novel objects as intact animals [27, 28]. Hence, the present finding is unlikely to be due to the robot merely acting as a local cue. Moreover, the lack of robot effects on distal place cells in occasions when rats acquired the pellet suggests that the heightened state of fear most likely affected distal place cells. Place cell firing and theta rhythm have been found to be modulated by the speed of animals as they run toward food [13, 29]. In the present study, in which the looming robot prevented the animals from procuring the pellet, neither the running speed nor the changes in running speed correlated with the changes in place cell firing and theta rhythm. However, given the significant difference in the relative outward speed between the proximal and distal regions and a trend toward a difference in the relative inward speed, the possibility of animals’ variable movements influencing place fields and theta power in the distal region cannot be excluded. It is now well documented that in mazes and other settings where animals search nonrandomly for reward, the task rules and directionality influence the place cell activity (e.g., [30–32]). Hence, different behaviors of the animal can produce dissimilar hippocampal neuronal activity in the same environment. The present finding of the robot-induced remapping of place cells only
when and where animals were most frightened is consistent with this multiple spatial and/or context reference frame view of place cells. What might then be the mechanism for hippocampal place cells to exhibit differential firing properties when animals are in safe (no/low fear) versus dangerous (high fear) locations? The stress hormones (e.g., glucocorticoids), released by the hypothalamic-pituitary-adrenal axis and implicated in mediating stress effects on the hippocampus [33, 34], are too slow in temporal (rise-fall) dynamics to account for the present distal-proximal differences in place fields and theta rhythm (see also [35]). An alternative possibility is the nature of interaction between the hippocampus’s processing of spatial (cognitive) information and the amygdala’s processing of fear (emotional) information [36], which is essential for animals to make optimal decisions in risky situations. In imminent threat situations (i.e., locus of high fear), the heightened amygdala-fear system might trigger activity changes in the hippocampus, allowing it to encode (gauge) distance of threat. Consistent with this notion, amygdala-lesioned rats showed no overt fear behavior to the robot, and their place fields in the vicinity of the robot were just as stable as those inside and near the nest. Other lines of evidence also indicate an amygdala-hippocampus interaction, such as (1) a previously fear-conditioned tone stimulus inducing place cell remapping that was blocked by inactivating the amygdala [37], (2) fear-conditioned stimuli and stress increasing theta synchrony between the amygdala and hippocampus [38–40], (3) amygdala stimulation decreasing the ensuing CA1 long-term potentiation (LTP) [41] and reducing the stability of place fields in CA1 place
Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved 1365
cells [35], and (4) amygdala lesions blocking stress-induced alterations of CA1 LTP and spatial memory [42]. To elucidate the nature of the amygdala-hippocampus interaction, future studies will need to determine whether the activity of fear encoding neurons in the amygdala scales the foraging distance and correlates with place cell remapping, as well as whether optogenetic silencing (and stimulating) amygdalar neurons prevents (and causes) the remapping of distal (and proximal) place fields. Though the remapping of place fields has previously been reported in rats randomly chasing pellets in a fear-conditioned context in which they received periorbital electric shocks [43], the present ‘‘ethological’’ analysis suggests that hippocampal spatial representation can be modified by innate fear signaling depending on the distance from threat, and thereby place cells map the psychological (fear) content onto the physical location of space to gate foraging decisions. Perhaps then one of the characteristics of anxiety disorders—the overwhelming sense of fear in nonthreatening outdoor contexts [44, 45]—can potentially arise from a dysfunctioning hippocampus that blurs the safety-danger boundaries. SUPPLEMENTAL INFORMATION Supplemental Information includes Supplemental Experimental Procedures, four figures, and three tables and can be found with this article online at http://dx.doi.org/10.1016/j.cub.2015.03.048. AUTHOR CONTRIBUTIONS E.J.K., M.P., M.K., S.G.P., J.C., and J.J.K. designed the research; E.J.K., M.P., and M.K. performed the research; E.J.K., M.P., M.K., S.G.P., J.C., and J.J.K. analyzed the data; and E.J.K., J.C., and J.J.K. wrote the paper. ACKNOWLEDGMENTS We thank Alisa J. Kim for editing the manuscript. This study was supported by NIH grant MH099073 (J.J.K.) and by the KIST intramural grant program (2E25210), Republic of Korea (J.C.). Received: December 16, 2014 Revised: March 3, 2015 Accepted: March 24, 2015 Published: April 16, 2015 REFERENCES 1. Bolles, R.C. (1970). Species-specific defense reactions and avoidance learning. Psychol. Rev. 77, 32–48. 2. Bolles, R.C., and Fanselow, M.S. (1980). A perceptual-defensive-recuperative model of fear and pain. Behav. Brain Sci. 3, 291–301. 3. Fanselow, M.S., and Lester, L.S. (1988). A functional behavioristic approach to aversively motivated behavior: Predatory imminence as a determinant of the topography of defensive behavior. In Evolution and Learning, R.C. Bolles and M.D. Beecher, eds. (Hillsdale: Erlbaum), pp. 185–211.
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Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved 1367
Alterations of Hippocampal Place Cells in Foraging Rats Facing a ‘‘Predatory’’ Threat Highlights
Authors
d
A ‘‘predatory’’ robot altered place cell stability and theta rhythm in foraging rats
Eun Joo Kim, Mijeong Park, ..., Jeiwon Cho, Jeansok J. Kim
d
Spatial correlations decreased as a function of distance from the safe nest
Correspondence
d
Amygdala lesions abolished the predatory robot effects on place cells
[email protected] (J.C.), [email protected] (J.J.K.)
In Brief While fear guides behaviors that help animals minimize exposures to threats in their habitat, the neural basis for discerning safe versus dangerous areas remains unknown. Using an ‘‘ethological’’ paradigm, Kim et al. show that hippocampal place cells exhibit a distance-gradient of danger in rats foraging for food when frightened by a predatory robot.
Kim et al., 2015, Current Biology 25, 1362–1367 May 18, 2015 ª2015 Elsevier Ltd All rights reserved http://dx.doi.org/10.1016/j.cub.2015.03.048
Current Biology
Report Alterations of Hippocampal Place Cells in Foraging Rats Facing a ‘‘Predatory’’ Threat Eun Joo Kim,1,5 Mijeong Park,3,4,5 Mi-Seon Kong,1 Sang Geon Park,3 Jeiwon Cho,3,4,* and Jeansok J. Kim1,2,* 1Department
of Psychology in Neuroscience University of Washington, 3921 West Stevens Way Northeast, Seattle, WA 98195-1525, USA 3Center for Neural Science, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 136-791, Korea 4Neuroscience Program, Korea University of Science and Technology, 217 Gajeong-ro, Daejeon 305-701, Korea 5Co-first author *Correspondence: [email protected] (J.C.), [email protected] (J.J.K.) http://dx.doi.org/10.1016/j.cub.2015.03.048 2Program
SUMMARY
Fear is an adaptive mechanism evolved to influence the primal decisions of foragers in ‘‘approach resource-avoid predator’’ conflicts [1–3]. To survive and reproduce, animals must attain the basic needs (food, water, shelter, and mate) while avoiding the ultimate cost of predation [4]. Consistent with this view, ecological studies have found that predatory threats cause animals to limit foraging to fewer places in their habitat and/or to restricted times [5–7]. However, the neurophysiological basis through which animals alter their foraging boundaries when confronted with danger remains largely unknown. Here, we investigated place cells in the hippocampus, implicated in processing spatial information and memory [8–10], in male Long-Evans rats foraging for food under risky situations that would be common in nature. Specifically, place cells from dorsal cornu ammonis field 1 (CA1) were recorded while rats searched for food in a semi-naturalistic apparatus (consisting of a nest and a relatively large open area) before, during, and after encountering a ‘‘predatory’’ robot situated remotely from the nest [11]. The looming robot induced remapping of place fields and increased the theta rhythm as the animals advanced toward the vicinity of threat, but not when they were around the safety of the nest. These neurophysiological effects on the hippocampus were prevented by lesioning of the amygdala. Based on these findings, we suggest that the amygdalar signaling of fear influences the stability of hippocampal place cells as a function of threat distance in rats foraging for food. RESULTS Hunger-motivated rats, implanted with tetrode arrays in the cornu ammonis field 1 (CA1) layer [12], underwent successive stages of nest habituation, foraging baseline, and robot testing
stages (Figures 1A and 1B; Supplemental Experimental Procedures). During the baseline, rats were repetitively allowed to leave the nest to procure a food pellet placed at a fixed location in the foraging area. Initially, rats spent considerable time exploring the novel foraging area before discovering the sizeable (0.5/1.0 g) pellet and instinctively bringing it back to the nest for consumption. Afterward, rats ran straight to the pellet and promptly brought it back to the nest, disregarding the area beyond the pellet location. Tetrodes were gradually advanced until complex spike cells were encountered (Figures 1C and 1D) and displayed consistent firing in the nest and/or in the foraging area. The robot testing consisted of ‘‘pre-robot,’’ ‘‘robot,’’ and ‘‘post-robot’’ recording sessions (five to ten foraging trials/session). From ten rats, a total of 78 place cells were recorded. They were classified into three types based on the region of maximal firing: inside the nest (‘‘nest cells’’), near the nest (‘‘proximal cells’’), and distant from the nest (‘‘distal cells’’) (Figure 2A). We found that place cells almost always fired during all three recording sessions, despite the animals’ inabilities to procure the pellet during the robot trials (Figure 2A; Table S1). When place cells were analyzed by performance of a pixel-by-pixel correlation of the maps from pre-robot versus post-robot and robot versus post-robot sessions (with matched foraging distances), all three regions of maximal firing did not differ in the correlation of the firing-rate maps (Figure 2B; F(2, 77) < 0.9, p > 0.4). Comparison between the firing-rate maps from the pre-robot and robot sessions, however, revealed a robot-induced remapping of place fields in the distal region (nearer to the threat), but not in the proximal and nest regions (farther from the threat; Figure 2B; F(2, 77) = 4.175, p < 0.05). Specifically, the pixel-by-pixel correlations of the distal cells were significantly reduced across the pre-robot versus robot sessions compared to the nest cells (p < 0.05), indicating that place cells altered their location-specific firing selective to the threat distance. This is corroborated by the relationship between the x position of the peak and spatial correlation (x position versus z0 pre versus robot, r = 0.265, p < 0.05; x position versus z0 robot versus post, r = 0.044, p = 0.705; x position versus z0 pre versus post, r = 0.033, p = 0.775; Figure 2C). Similarly, the peak distance of the firing-rate maps between the pre-robot and robot sessions was higher in the distal cells compared to the nest and proximal cells (p < 0.01; Figure S1A). Also, in response to the robot, the peak x positions of the distal cells
1362 Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved
Figure 1. Predatory Robot and Place Cells (A) A photograph of a rat in the foraging apparatus. (B) Illustrations of the experimental design. (C) A photomicrograph of tetrodes implants in the CA1 area (arrowhead). (D) Representative waveforms of place cells.
significantly shifted toward the nest direction, whereas the nest and proximal cells showed no reliable directional bias (Figure S1B). The predatory robot also differentially affected the hip-
pocampal theta rhythm, which is implicated in selective attention, arousal, and decision making [13], in a distance-dependent manner. The power spectral density of theta frequency (6–10 Hz; cf. [14–16]) from hippocampal place cells (Figure 3A) revealed that the theta power increased during the robot session compared to the pre-robot session only in the distal cells (p = 0.029; Figure 3B). These distance-dependent differences in place fields and theta power cannot be accounted solely by the change in the animals’ running speed between no-robot and robot sessions because the overall running speeds in distal and proximal foraging areas during the robot session were not different (Table S1). Also, the running speed correlated with neither the firing rate nor the theta power (Table S2). The directionality of the movement was taken into account by subdividing the movement speed as the animal left the nest toward the food (i.e., proximaloutward speed and distal-outward speed) and fled to the nest (i.e., distal-inward speed and proximal-inward speed; R4 pixel bins). Overall, the outward movement was slower than inward movement (robotout, 23.2 ± 2.01; robotin, 37.6 ± 4.33; paired t = 4.27, p < 0.001). However, the movement speeds in both directions were not correlated with the average firing rate (outward speed versus firing rate, r = 0.096, p = 0.557; inward speed versus firing rate, r = 0.151, p = 0.351). To clarify the relationship between the speed change or acceleration and place cells remapping between pre-robot and robot sessions, we calculated the relative running speed [the amount of speed change; (speedrobot speedpre) / speedpre] for each direction (inward and outward). The outward speed change did not differ from the inward speed change between the pre-robot and robot sessions
Figure 2. Distance to the Robot Affects the Stability of Place Cells (A) Example place fields from nest, proximal, and distal cells during pre-robot, robot, and post-robot sessions. The color scale (red, maximal firing; blue, no spike) corresponds to the firing rate for each unit. The numerical value represents the peak firing rate for each session. (B) Differences in the z0 value between sessions inside the nest, proximal to the nest, and distal to the nest. Data are represented as mean ± SEM. *p < 0.05, Bonferroni comparison. (C) Scatter plots showing x positions of peak firing during the pre-robot session versus the spatial correlations (z0 ) between sessions. See also Figures S1, S2, and S4 and Tables S1 and S2.
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Figure 3. Distance to the Robot Affects the Theta Rhythm of Place Cells (A) The population-averaged power spectrum of the nest, proximal, and distal cells. (B) Differences in the theta band (6–10 Hz; gray sections in A) across the pre-robot (dark gray), robot (orange), and post-robot (cyan) sessions. Data are represented as mean ± SEM. *p < 0.05, Bonferroni comparison.
(paired t = 1.48, p = 0.15; Figure S2A). When the speed change was compared between the proximal and distal regions, the relative proximal-outward speed was significantly lower than the relative distal-outward speed (independent t = 5.64, p < 0.001; Figure S2B), and the relative distal-inward speed was not significantly higher than the relative proximal-inward speed (independent t = 1.80, p = 0.083). However, the spatial correlation (z0 ) was related to neither the relative inward nor outward speed (inward relative speed versus z0 , r = 0.030, p = 0.853; outward relative speed versus z0 , r = 0.25; p = 0.125; Figure S2C). Even when the correlational analyses were limited to the distal location data, which showed the biggest behavioral changes between pre-robot and robot sessions, there were no significant influences of movement difference (the amount of speed change) on the spatial correlation of distal cells for outward direction in the distal location (outward relative speed versus z0 , r = 0.282, p = 0.138) or on the average firing rate (outward relative speed versus firing rate, r = 0.087, p = 0.652). In addition, both the inward and outward movement speeds were not correlated with the theta power during the robot session (inward speed versus theta power, r = 0.067, p = 0.680; outward speed versus theta power, r = 0.065, p = 0.689; Figure S2D). Altogether, these results parallel the behavioral finding [11] that normal rats often failed to procure pellets placed beyond 25 cm from the nest, which approximates the nest-to-proximal zone of the present study. Previous studies have shown that amygdalar lesions and inactivations abolished the foraging rats’ fear of the looming robot [11], whereas amygdalar stimulation evoked the same fleeing response in naive rats in absence of the robot [17]. To test whether the robot-induced instability of place fields around the source of threat is mediated via the amygdala-fear system, we recorded place cells in amygdala-lesioned rats (n = 4; Table S3). These rats easily obtained the pellets despite the surging robot (Figure S3A), and the pixel-by-pixel correlation analysis showed that place fields in the distal area remained stable across all recording sessions (Figure 4A) and were comparable to the nest and proximal place fields (F < 2.19, p > 0.12; Figures 4B and S3B). Similarly, there was no difference between the cell types
in the peak distance across sessions (c2 < 1.778, p > 0.411; Figure S3C). No reliable correlation was observed between the peak x position during the pre-robot session and the spatial correlation across sessions (r < 0.213, p > 0.08; Figures 4C and S3D). In addition, the theta power of distal cells in amygdala-lesioned rats (Figure 4D) did not differ across sessions (F(2, 22) = 0.279, p = 0.759; Figure 4E). Although the success rate of procuring food was significantly lower in amygdala-intact rats (14.3% ± 4.13%; mean ± SEM) compared to amygdala-lesioned rats (97.9% ± 1.57%), there were times when few intact rats managed to get the pellet during the robot test (Figure S3A). These data, when analyzed separately, revealed that both the difference in place field stability between distal versus proximal and nest (F < 0.799, p > 0.459) and the correlation between x positions and spatial correlations (z0 pre versus robot, r = 0.146, p = 0.424) were no longer significant (Figures S4A and S4B). Hence, the robot effects on distal place cells emerged when animals were unable to procure the pellet (high state of fear), but not in cases where animals were able to attain the pellet (lower state of fear). DISCUSSION In the present study, the dynamics of hippocampal place cell spikes were recorded under an ecologically relevant ‘‘approach food-avoid predator’’ setting in which the adaptive functions of fear most likely evolved [1, 2, 18]. Under this condition, we found that while place fields were stable inside and nearby the nest (loci of no/low fear), place cells showed instable firing fields at locations neighboring the threat area (locus of high fear). Likewise, the theta rhythm (6–10 Hz) in the hippocampus, which is associated with various behaviors [13], was selectively increased near the vicinity of the robot. These observations suggest a possible scaling relationship between the magnitude of fear, which varies in a relation to the nest-foraging distance, and the stability of hippocampal place fields. Although the looming robot-evoked fleeing responses (effects blocked by amygdalar lesions) suggest fear as the cause of distal place cell instability, an alternative explanation for the finding is the local cue (salience and/or novelty) aspect of the robot signaled by the amygdala. For example, the introduction (or displacement) of a local cue in the environment has been shown to alter a subset of hippocampal place fields ([19–21]; but see [22–24]). In these studies, animals came in physical contact with (and sniffed [21]) the cue or the location where the cue is
1364 Current Biology 25, 1362–1367, May 18, 2015 ª2015 Elsevier Ltd All rights reserved
Figure 4. Amygdalar Lesions Abolished the Predatory Robot Effects on Distal Place Cell Stability and Theta Power (A) Distal cells recorded from the amygdala-lesioned rats during pre-robot, robot, and post-robot sessions. The numerical value represents the peak firing rate for each session. (B) Comparisons of the z0 value between the pre-robot and robot sessions in nest (green), proximal nest (purple), and distal nest (red) areas. Data are represented as mean ± SEM. (C) A scatter plot showing x positions of peak firing during the pre-robot session versus the spatial correlations (z0 ) between the pre-robot and robot sessions. (D) The population-averaged power spectrums of nest, proximal, and distal cells in the amygdala-lesioned rats. (E) Comparisons of the theta band (6–10 Hz; gray sections in A) across the pre-robot (dark gray), robot (orange), and post-robot (cyan) sessions. Data are represented as mean ± SEM. See also Figure S3 and Table S3.
no longer present. In contrast, rats in the present study never came close to the remotely placed robot because the robot’s surging motion mainly caused rats to flee into the nest. The possibility of the amygdala’s role in salience and/or novelty [25, 26] influencing hippocampal place fields cannot be excluded, but several studies have shown that amygdala-lesioned rats spent comparable time exploring novel objects as intact animals [27, 28]. Hence, the present finding is unlikely to be due to the robot merely acting as a local cue. Moreover, the lack of robot effects on distal place cells in occasions when rats acquired the pellet suggests that the heightened state of fear most likely affected distal place cells. Place cell firing and theta rhythm have been found to be modulated by the speed of animals as they run toward food [13, 29]. In the present study, in which the looming robot prevented the animals from procuring the pellet, neither the running speed nor the changes in running speed correlated with the changes in place cell firing and theta rhythm. However, given the significant difference in the relative outward speed between the proximal and distal regions and a trend toward a difference in the relative inward speed, the possibility of animals’ variable movements influencing place fields and theta power in the distal region cannot be excluded. It is now well documented that in mazes and other settings where animals search nonrandomly for reward, the task rules and directionality influence the place cell activity (e.g., [30–32]). Hence, different behaviors of the animal can produce dissimilar hippocampal neuronal activity in the same environment. The present finding of the robot-induced remapping of place cells only
when and where animals were most frightened is consistent with this multiple spatial and/or context reference frame view of place cells. What might then be the mechanism for hippocampal place cells to exhibit differential firing properties when animals are in safe (no/low fear) versus dangerous (high fear) locations? The stress hormones (e.g., glucocorticoids), released by the hypothalamic-pituitary-adrenal axis and implicated in mediating stress effects on the hippocampus [33, 34], are too slow in temporal (rise-fall) dynamics to account for the present distal-proximal differences in place fields and theta rhythm (see also [35]). An alternative possibility is the nature of interaction between the hippocampus’s processing of spatial (cognitive) information and the amygdala’s processing of fear (emotional) information [36], which is essential for animals to make optimal decisions in risky situations. In imminent threat situations (i.e., locus of high fear), the heightened amygdala-fear system might trigger activity changes in the hippocampus, allowing it to encode (gauge) distance of threat. Consistent with this notion, amygdala-lesioned rats showed no overt fear behavior to the robot, and their place fields in the vicinity of the robot were just as stable as those inside and near the nest. Other lines of evidence also indicate an amygdala-hippocampus interaction, such as (1) a previously fear-conditioned tone stimulus inducing place cell remapping that was blocked by inactivating the amygdala [37], (2) fear-conditioned stimuli and stress increasing theta synchrony between the amygdala and hippocampus [38–40], (3) amygdala stimulation decreasing the ensuing CA1 long-term potentiation (LTP) [41] and reducing the stability of place fields in CA1 place
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cells [35], and (4) amygdala lesions blocking stress-induced alterations of CA1 LTP and spatial memory [42]. To elucidate the nature of the amygdala-hippocampus interaction, future studies will need to determine whether the activity of fear encoding neurons in the amygdala scales the foraging distance and correlates with place cell remapping, as well as whether optogenetic silencing (and stimulating) amygdalar neurons prevents (and causes) the remapping of distal (and proximal) place fields. Though the remapping of place fields has previously been reported in rats randomly chasing pellets in a fear-conditioned context in which they received periorbital electric shocks [43], the present ‘‘ethological’’ analysis suggests that hippocampal spatial representation can be modified by innate fear signaling depending on the distance from threat, and thereby place cells map the psychological (fear) content onto the physical location of space to gate foraging decisions. Perhaps then one of the characteristics of anxiety disorders—the overwhelming sense of fear in nonthreatening outdoor contexts [44, 45]—can potentially arise from a dysfunctioning hippocampus that blurs the safety-danger boundaries. SUPPLEMENTAL INFORMATION Supplemental Information includes Supplemental Experimental Procedures, four figures, and three tables and can be found with this article online at http://dx.doi.org/10.1016/j.cub.2015.03.048. AUTHOR CONTRIBUTIONS E.J.K., M.P., M.K., S.G.P., J.C., and J.J.K. designed the research; E.J.K., M.P., and M.K. performed the research; E.J.K., M.P., M.K., S.G.P., J.C., and J.J.K. analyzed the data; and E.J.K., J.C., and J.J.K. wrote the paper. ACKNOWLEDGMENTS We thank Alisa J. Kim for editing the manuscript. This study was supported by NIH grant MH099073 (J.J.K.) and by the KIST intramural grant program (2E25210), Republic of Korea (J.C.). Received: December 16, 2014 Revised: March 3, 2015 Accepted: March 24, 2015 Published: April 16, 2015 REFERENCES 1. Bolles, R.C. (1970). Species-specific defense reactions and avoidance learning. Psychol. Rev. 77, 32–48. 2. Bolles, R.C., and Fanselow, M.S. (1980). A perceptual-defensive-recuperative model of fear and pain. Behav. Brain Sci. 3, 291–301. 3. Fanselow, M.S., and Lester, L.S. (1988). A functional behavioristic approach to aversively motivated behavior: Predatory imminence as a determinant of the topography of defensive behavior. In Evolution and Learning, R.C. Bolles and M.D. Beecher, eds. (Hillsdale: Erlbaum), pp. 185–211.
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