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An inhibitory hippocampal–thalamic pathway modulates remote memory retrieval

Abstract

Memories are supported by distributed hippocampal–thalamic–cortical networks, but the brain regions that contribute to network activity may vary with memory age. This process of reorganization is referred to as systems consolidation, and previous studies have examined the relationship between the activation of different hippocampal, thalamic, and cortical brain regions and memory age at the time of recall. While the activation of some brain regions increases with memory age, other regions become less active. In mice, here we show that the active disengagement of one such brain region, the anterodorsal thalamic nucleus, is necessary for recall at remote time-points and, in addition, which projection(s) mediate such inhibition. Specifically, we identified a sparse inhibitory projection from CA3 to the anterodorsal thalamic nucleus that becomes more active during systems consolidation, such that it is necessary for contextual fear memory retrieval at remote, but not recent, time-points post-learning.

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Fig. 1: ADn activity is necessary for recall of recently acquired contextual fear memory.
Fig. 2: Identification of anatomical projections to the ADn.
Fig. 3: Identification of inhibitory projections to the ADn.
Fig. 4: CA3 inhibitory cells projecting to the ADn become more active at the remote time-point post-training.
Fig. 5: CA3 inhibitory cells projecting to the ADn are necessary for the recall of remote memory.

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Data availability

The data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by Canadian Institutes of Health Research (CIHR) grants to P.W.F. (grant no. FDN143227) and S.A.J. (grant no. MOP74650). F.X. was supported by fellowships from NSERC and Biological Sleep and Rhythms (CIHR). G.V. was supported by the Biological Sleep and Rhythms (CIHR) fellowship. A.I.R. was supported by fellowships from NSERC and NIMH (grant no. 1 F31 MH120920-01). L.M.T. was supported by fellowships from The Hospital for Sick Children RestraComp and NSERC. P.W.F. and S.A.J. are senior fellows in the Child Brain & Development Program and the Brain, Mind & Consciousness programs, respectively, at the Canadian Institute for Advanced Research.

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G.V., F.X., A.I.R., L.M.T., S.A.J. and P.W.F. designed the experiments. G.V., F.X., A.I.R. and L.M.T. conducted the histology and behavioral experiments, and associated data analysis. A.I.R. and L.M.T. performed an independent replication of the main behavioral experiment. P.W.F., F.X., G.V., A.I.R. and L.M.T. wrote and edited the manuscript.

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Correspondence to Paul W. Frankland.

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Peer review information Nature Neuroscience thanks Magdalena Sauvage, Seralynne Vann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Analysis of co-activation of ADn with 83 other brain regions following recent vs. remote fear memory retrieval.

a, Following recent fear memory recall, ADn activity was positively correlated with activity in the majority of the other 83 brain regions. (bars: correlation between ADn and a given region; green line and shaded region: mean correlation between other 83 non-ADn brain regions and a given region ± s.e.m,). b, At the remote time point, ADn activity became strongly inversely correlated with activity in the majority (78/83) of other 83 brain regions. (bars: correlation between ADn and a given region; blue line and shaded region: mean correlation between other 83 brain regions combined and a given region ± s.e.m.). Data were obtained from Wheeler et al., 201311.

Extended Data Fig. 2 Characterization of ADn cell type.

Representative images showing immunohistochemical staining in ADn of WT home cage mice with a, inhibitory cell marker GAD67 (repeated in n = 3), or b, excitatory cell marker aCamKII (repeated in n = 3; scale bar: 100 μm).

Extended Data Fig. 3 Identification of anatomical projections to the ADn.

a, WT mice were micro-infused with Retrobeads in the ADn, and b, neurons in anterior cingulate cortex (ACC), retrosplenial cortex (RSP), and presubiculum (PRE) were retrogradely labeled (n = 3). Examples from additional mice are included. c, WT mice were micro-infused with the retrograde tracer cholera toxin subunit B (CTB) in the ADn, and d, neurons in retrosplenial cortex (RSP), and presubiculum (PRE) were retrogradely labeled (n = 3). Additional examples of ADn infusion site and retrogradely labeled CA3 are also shown. e, WT mice were micro-infused with the anterograde tracer PHA-L in the CA3, and f, in addition to ipsilateral ADn (Fig. 2f), ipsilateral CA1, contralateral CA1 and CA3 were anterogradely labeled, while much less labeling was observed in contralateral ADn (n = 4). An additional example of anterograde labeling in ADn is shown. g-h, To visualize specifically CA3-ADn projections, WT mice were micro-infused with AAV-DIO-mCherry bilaterally in CA3 and AAVrg-Cre-EGFP unilaterally in ADn (n = 4). Majority of the CA3-ADn (mCherry+) cells were visualized in CA3 ipsilateral to the site of ADn infusion. To see whether anatomical projections from other regions to ADn are inhibitory, different VGAT-Cre mice were micro-infused with AAV-DIO-EYFP in i-j, retrosplenial cortex (RSP), k-l, anterior cingulate cortex (ACC), or m-n, presubiculum (PRE) (n = 3 for each region). Unlike the CA3 (Fig. 3c,d), none of these regions showed terminal projections in the ADn (blue scale bars: 100 μm, white scale bars: 50 μm).

Extended Data Fig. 4 Independent replication experiment showing that CA3 inhibitory cells projecting to the ADn are necessary for the recall of remote memory.

a, VGAT-Cre mice were micro-infused with AAV-DIO-iC++-EYFP or AAV-DIO-EYFP virus in CA3 and optical fibres were implanted in the ADn, to optogenetically inhibit the CA3-ADn projection during fear memory test, at 1 or 28 days post-training. b, At 1 day test, iC++- and EYFP-infused mice froze equally during light-OFF and light-ON epochs (iC++ n = 9; EYFP n = 8; two-sided Mann-Whitney test iC++ versus EYFP, P = 0.40; OFF: two-sided Wilcoxon signed rank test iC++ versus EYFP, P = 0.82; ON: two-sided Wilcoxon signed rank test iC++ versus EYFP, P = 0.28). c, At 28 day test, iC++- and EYFP-infused mice froze equally during light-OFF epoch (3 minutes duration), but iC++-infused mice showed reduced freezing in comparison to EYFP-infused mice during light-ON epoch (3 minute duration) (iC++ n = 12; EYFP n = 10; two-way repeated measures ANOVA iC++ versus EYFP x light-OFF versus light-ON; interaction, F1,20 = 5.35, P = 0.031; light-OFF versus light-ON, F1,20 = 0.43, P = 0.52; iC++ versus EYFP, F1,20 = 3.45, P = 0.078; post hoc Bonferroni’s test, light-OFF iC++ versus EYFP P > 0.99, light-ON iC++ versus EYFP P = 0.015). d, At 1 day, iC++-infused mice showed equivalent level of c-Fos expression in the ADn (normalized to mean expression level in home cage control mice (n = 16)), in comparison to EYFP-infused control mice. But at 28 day, iC++-infused mice showed elevated level of c-Fos expression in the ADn, in comparison to controls. (1 day: iC++ n = 7; EYFP n = 12; 28 day: iC++ n = 5; EYFP n = 7; two-way ANOVA iC++ versus EYFP x 1 day versus 28 day; interaction, F1,27 = 18.39, P = 0.0002; 1 day versus 28 day, F1,27 = 2.26, P = 0.14; iC++ versus EYFP, F1,27 = 23.34, P < 0.0001; post hoc Bonferroni’s test, 1 day iC++ versus EYFP P > 0.99, 28 day iC++ versus EYFP P < 0.0001). e, Both iC++ and EYFP groups froze significantly more during test (first 3 minutes) at 1 day than pre-shock period during training (iC++ n = 14; EYFP n = 11; iC++: two-sided Wilcoxon matched-pair signed rank test pre-shock versus 1 day test, P = 0.0001; EYFP: two-sided Wilcoxon matched-pair signed rank test pre-shock versus 1 day test, P = 0.001). f, Both iC++ and EYFP groups froze significantly higher during test (last 3 minutes) at 28 day than pre-shock period during training (iC++ n = 18; EYFP n = 17; iC++: two-sided Wilcoxon matched-pair signed rank test pre-shock versus 28 day test, P < 0.0001; EYFP: two-sided Wilcoxon matched-pair signed rank test pre-shock versus 28 day test, P < 0.0001). g. VGAT-Cre mice trained without shocks and tested the following day showed baseline (floor) level freezing (n = 10; two-sided paired t-tests t9 = 1.56, P = 0.15). h. VGAT-Cre mice were habituated to the training context for 5 days (twice a day, 10 min each) before contextual fear conditioning. Mice showed significantly lower levels of freezing following this latent inhibition protocol, in comparison to the 1 day habituation protocol (1 day habituation (1D Hab): n = 7; 5 day habituation (5D Hab): n = 10; two-sided t-tests t15 = 2.38, P = 0.03). Data are individual mouse, or mean ± s.e.m. (* P < 0.05, *** P < 0.001, **** P < 0.0001).

Extended Data Fig. 5 Inhibition of CA3-ADn inhibitory pathway does not alter locomotor activity in open field test.

a, VGAT-Cre mice were micro-infused with AAV-DIO-iC++-EYFP or AAV-DIO-EYFP virus in CA3 and optical fibres were implanted in the ADn, to optogenetically inhibit the CA3-ADn projection during test in a novel open field. b, iC++- and EYFP-infused mice showed similar levels of distance traveled during the light-OFF and light-ON epochs (3 minute duration) (iC++ n = 4; EYFP n = 4; two-way repeated measures ANOVA iC++ versus EYFP x light-OFF versus light-ON; interaction, F1,6 = 0.92, P = 0.38; light-OFF versus light-ON, F1,6 = 2.31, P = 0.179; iC++ versus EYFP, F1,6 = 0.002, P = 0.97). c, VGAT-Cre mice were micro-infused with AAV-DIO-iC++-EYFP or AAV-DIO-EYFP virus in CA3 and optical fibres were implanted in the ADn. On day 1, mice were pre-exposed to open field chamber without light (6 min), then on day 2, the CA3-ADn projection was optogenetically inhibited by turning on the laser during the last 3 min of the open field test, to assess the effect of inhibition on locomotor activity in a familiar environment. To assess the effect of inhibition on locomotor activity in a second familiar environment, 1 day after open field test, mice were pre-exposed to the fear conditioning chamber without shocks and without light (6 min), and then 24 hours later, the CA3-ADn projection was optogenetically inhibited by turning on the laser during the last 3 min of the fear test. d, iC++- and EYFP-infused mice showed similar levels of distance traveled during the first and last 3 minutes of open field pre-exposure on day 1 without light (iC++ n = 6; EYFP n = 6; two-way repeated measures ANOVA iC++ versus EYFP x first-3-min versus last-3-min; interaction, F1,10 = 2.05, P = 0.18; first-3-min versus last-3-min, F1,10 = 48.40, P < 0.0001; iC++ versus EYFP, F1,10 = 1.08, P = 0.32). e, iC++- and EYFP-infused mice showed similar levels of distance traveled during light-OFF and light-ON periods of open field test on day 2 (iC++ n = 6; EYFP n = 6; two-way repeated measures ANOVA iC++ versus EYFP x light-OFF versus light-ON; interaction, F1,10 = 0.54, P = 0.48; light-OFF versus light-ON, F1,10 = 0.15, P = 0.70; iC++ versus EYFP, F1,10 = 0.11, P = 0.74). f, iC++- and EYFP-infused mice showed similar levels of freezing during light-OFF and light-ON periods of fear test 1 day after fear chamber pre-exposure without shocks (iC++ n = 6; EYFP n = 6; two-way repeated measures ANOVA iC++ versus EYFP x light-OFF versus light-ON; interaction, F1,10 = 0.00, P = 0.77; light-OFF versus light-ON, F1,10 = 3.40, P = 0.09; iC++ versus EYFP, F1,10 = 0.00, P = 0.76). Data are individual mouse, or mean ± s.e.m.

Extended Data Fig. 6 CA3-ADn pathway is recruited from recent to remote fear memory recall.

a, ADn is activated and necessary for recent memory retrieval. At this time, the inhibitory cells that project from CA3 to the ADn are relatively inactive. b, At the remote memory retrieval, inhibitory cells that project from CA3 to the ADn are actively engaged to suppress the activity in ADn. The suppression of ADn activity is necessary for remote memory retrieval.

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Vetere, G., Xia, F., Ramsaran, A.I. et al. An inhibitory hippocampal–thalamic pathway modulates remote memory retrieval. Nat Neurosci 24, 685–693 (2021). https://doi.org/10.1038/s41593-021-00819-3

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