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Bidirectional switch of the valence associated with a hippocampal contextual memory engram

Nature volume 513, pages 426–430 (2014)Cite this article

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Abstract

The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique3,4. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.

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Figure 1: Fear and reward engram reactivation, both in the DG and the BLA, drives place avoidance and place preference, respectively.
Figure 2: The valence associated with the DG engram is reversed after induction with the unconditioned stimulus of opposite value.
Figure 3: DG to BLA functional connectivity changes after induction.
Figure 4: Memory induction alters naturally cued fear memory.

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Acknowledgements

We thank X. Zhou, C. Potter, D. Plana, J. Martin, M. Tsitsiklis, H. Sullivan, W. Yu and A. Moffa for help with the experiments; K. L. Mulroy, T. Ryan and D. Roy for comments and discussions on the manuscript, and all the members of the Tonegawa laboratory for their support. This work was supported by the funds from the RIKEN Brain Science Institute, the Howard Hughes Medical Institute and The JPB Foundation to S.T., and the National Institutes of Health Pre-doctoral Training Grant T32GM007287 to J.K.

Author information

Author notes

  1. Roger L. Redondo and Joshua Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology and Department of Brain and Cognitive Sciences, RIKEN–MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Roger L. Redondo, Joshua Kim, Autumn L. Arons, Steve Ramirez, Xu Liu & Susumu Tonegawa

  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Roger L. Redondo, Autumn L. Arons, Xu Liu & Susumu Tonegawa

Authors
  1. Roger L. Redondo
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  2. Joshua Kim
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  3. Autumn L. Arons
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  4. Steve Ramirez
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  5. Xu Liu
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  6. Susumu Tonegawa
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Contributions

R.L.R., J.K. and S.T. contributed to the study design. R.L.R., J.K. and S.R. contributed to the data collection. X.L. cloned all constructs. R.L.R., J.K. and A.L.A. conducted the surgeries. R.L.R. and J.K. conducted the behavioural experiments. R.L.R. conducted the functional connectivity experiments. J.K. conducted the reversal experiments. R.L.R. contributed to the setup of the behavioural and optogenetic apparatus and programmed the behavioural software to run the experiments. R.L.R., J.K. and S.T. wrote the paper. All authors discussed and commented on the manuscript.

Corresponding author

Correspondence to Susumu Tonegawa.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Light-induced avoidance and preference tests.

a, b, Shock place avoidance test. a, After the 0–3 min baseline (BSL), the most preferred zone was established as the target zone. Wild-type, shock mice (n = 11) received foot shocks (0.15 mA DC (direct current), 2 s duration every 5 s) when entering the target zone during the on phases (3–6 and 9–12 min). No shocks were delivered during the off phase (6–9 min). Wild-type, no shock mice (n = 24) received no shocks. b, The difference score was lower in the wild-type, shock mice compared to wild-type, no shock (t41 = 3.76, P < 0.001). c, d, Optogenetic place avoidance (OptoPA) test. c, Mice were allowed to explore the arena during baseline and the preferred side determined as the target zone. Light stimulation (20 Hz, 15 ms pulse width, 473 nm, > 10 mW) was applied when the mice entered the target zone during the on phases. Light stimulation was not delivered during the off phase. d, The difference score was lower in the DG ChR2 mice (n = 48) compared to DG mCherry-only mice (n = 39) (t85 = 3.55, P < 0.001). e, f, Female place preference test. e, After the 0–3 min baseline, the less preferred zone was established as the target zone. During the on phases (3–6 and 9–12 min), a corral containing a female was placed in the less preferred zone (target zone) and an empty corral was placed on the opposite side. Corrals, and the female, were removed during the off phase. f, Mice (n = 24) increased the time spent in the target zone compared to mice presented with two empty receptacles (n = 8) (t30 = 2.81, P < 0.01). g, h, Optogenetic place preference (OptoPP) test. g, Reward-labelled mice were allowed to explore the arena during baseline and the less preferred zone designated as the target zone. Light stimulation (20 Hz, 15 ms pulse width, 473 nm, > 10 mW) was applied while the subject was in the target zone of the chamber at the 3–6 min and 9–12 min epochs (on phase). h, The difference score was increased in the DG ChR2 mice (n = 54) compared to DG mCherry-only mice (n = 36) (t88 = 4.361, P < 0.001). a, c, e, g (right panel), Representative tracks for experimental animals. Dots mark the position of the animal every 5 video frames and accumulate where the mice spend more time.

Extended Data Figure 2 Light stimulation in the OptoPA and OptoPP tests has no effect during habituation.

a, Day 1 OptoPA habituation. There are no within group differences in the average duration spent in the target zone during the average of the baseline and off phases (off) and the averages of the two light on phases (on) during day 1 habituation in the OptoPA test, even though there is an overall difference between the two types of phases (F1,173 = 6.46, P < 0.05, 6 NS multiple comparisons. DG ChR2 n = 48; DG mCherry-only n = 39; DG ChR2, no US on day 3 n = 17; BLA ChR2 n = 32; BLA mCherry-only n = 27; BLA ChR2, no US on day 3 n = 27). b, Day 1 OptoPP habituation. There are no within group differences in the average time duration spent in the target zone during the average of the baseline and off phases (off) and the average of the two light on phases (on) during day 1 habituation in the OptoPP test, even though there is an overall difference between the two types of phases (F1,195 = 8.06, P < 0.01, 6 NS multiple comparisons. DG ChR2 n = 54; DG mCherry-only n = 36; DG ChR2, no US on day 3 n = 24; BLA ChR2 n = 35; BLA mCherry-only n = 31; BLA ChR2, no US on day 3 n = 21). c, d, There are no differences between experimental groups and wild-type mice tested without light stimulation. c, In the OptoPA test, the difference scores (on minus off) are similar between experimental groups (same as panel a) and wild-type mice (n = 33) that did not receive light stimulation (F6,205 = 0.19, NS). d, In the OptoPP test, the difference scores (on minus off) are similar between experimental groups (same as panel b) and wild-type mice (n = 33) that did not receive light stimulation (F6,227 = 0.21, NS).

Extended Data Figure 3 Fibre positions in DG and BLA.

a, Representative example of the fibre location and the expression of the ChR2–mCherry construct in the DG. b, Representative example of the fibre location and the expression of the ChR2–mCherry construct in the BLA.

Extended Data Table 1 Mice chose a preferred side on day 9 irrespective of their choice of preferred side on day 5 in both fear-to-reward and reward-to-fear experiments
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Redondo, R., Kim, J., Arons, A. et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014). https://doi.org/10.1038/nature13725

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