Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation
- Department of Cognitive Psychology, University of Hamburg, Germany
- Department of Psychiatry and Psychotherapy, University Medical Center Hamburg Eppendorf, Germany
- Department of Psychology and Wu Tsai Neurosciences Institute, United States
Figures
Figure 1
Experimental task.
The impact of post-retrieval yohimbine and hydrocortisone on subsequent memory was tested in a 3 d paradigm, recording fMRI data on all days. On Day 1, participants encoded word-picture pairs across three runs and then underwent an immediate cued recall test. On Day 2, 24 hr later, participants started with a 10 min resting-state fMRI scan, followed by the oral administration of 20 mg yohimbine (YOH), 20 mg hydrocortisone (CORT), or a placebo (PLAC). Thereafter, in the Memory Cueing task, half of the word-picture pairs were cued by presenting the corresponding word; Day 2 ended with another 10 min resting-state scan. On Day 3, again 24 hr later, participants completed a final cued recall test including word cues for all 144 pairs from Day 1 encoding, half of which had been cued and half of which had not been cued on Day 2, along with 152 new foils.
Figure 2
Trial-wise pattern reinstatement during Encoding and the Day 2 Memory Cueing task.
(A) To derive an index of visual category reinstatement in the ventral temporal cortex (VTC), an independent localizer task was conducted at the end of Day 3. During this task, pictures of scenes and objects were presented block-wise to participants. (B) The resulting neural patterns of both categories were then used to train an L2-regularized logistic regression. This function served to classify trial-wise patterns during the Day 1 Encoding task as well as the Day 2 Memory Cueing task, while also providing the strength of category-level online reinstatement (quantified as logits). Associative cat. hits = associative category hits.
Figure 3
ffective noradrenergic and glucocorticoid action after Day 2 memory cueing.
Systolic blood pressure (A) and salivary cortisol (B) did not differ between groups before or immediately after the Memory Cueing task. However, 70 min after pill intake, systolic blood pressure was significantly higher in the yohimbine (YOH; n = 21) group relative to the placebo (PLAC; n = 20) group. Conversely, salivary cortisol was significantly higher in the hydrocortisone (CORT; n = 21) group relative to PLAC starting 40 min after pill intake. Light yellow shades indicate the pre- and post-memory cueing resting-state fMRI scan periods. Data represent means (±SE). ***p<0.001, **p<0.01.
Figure 4
Subsequent memory performance on Day 3, split for cued and correct (Day 2), and uncued trials.
Average memory performance (associative d’) was significantly increased for cued and correct (Day 2) trials compared to uncued trials. This effect was, however, unaffected by the pharmacological manipulation. Data represent means (± SE). ***p<0.001.
Figure 5
Subsequent memory impairment by noradrenergic activation depends on hippocampal and ventral temporal cortex (VTC) online reactivation.
(A) Reactivation strength was initially indexed using trial-wise reaction times (memory confidence) during the Day 2 Memory Cueing task. In all three groups, the probability of a later associative category hit on Day 3 was greater on trials for which there were shorter reaction times/higher confidence during recall on Day 2. However, post-retrieval adrenergic activation (yohimbine, YOH group; n = 21) differentially impaired subsequent memory following high confidence Day 2 retrieval, suggesting that trials which are reactivated more strongly prior to noradrenergic activation are affected most by the intervention. (B) Such reductions in the probability of later associative category hits on Day 3 were further related to high hippocampal activity during Day 2 memory cueing specifically for the YOH group. Notably, trials which were retrieved with low confidence during memory cueing were not affected by any drug. (C) Further reductions in the probability of later associative category hits on Day 3 were observed for strong category-level reinstatement in the VTC in conjunction with strong hippocampal univariate activity in the YOH group on Day 2, which differed from the relationships seen in the placebo (PLAC; n = 20) and hydrocortisone (CORT; n = 21) groups. As such, post-retrieval adrenergic activation (YOH group) impaired subsequent memory as a function of the strength of memory reactivation prior to drug efficacy. *p<0.05,***p<0.001. Ass. cat. hit = associative category hit. Colored shades represent.95 confidence intervals.
Tables
Appendix 1—table 1
Memory performance and reaction times across experimental days.
| PLAC | YOH | CORT | |
|---|---|---|---|
| Day 1 (cued and correct on Day 2) | |||
| Hits (%) | 49.72 (1.64) | 43.19 (2.15) | 49.59 (2.82) |
| Dprime | 1.21 (0.07) | 1.01 (0.07) | 1.25 (0.11) |
| Reaction time (s) | 2.29 (0.07) | 2.40 (0.07) | 2.39 (0.07) |
| Day 1 (not cued on Day 2) | |||
| Hits (%) | 49.38 (1.96) | 41.77 (2.11) | 50.64 (2.64) |
| Dprime | 1.19 (0.09) | 0.96 (0.07) | 1.17 (0.10) |
| Reaction time (s) | 2.27 (0.07) | 2.41 (0.09) | 2.44 (0.07) |
| Day 2 (cued and correct on Day 2) | |||
| Hits (%) | 68.85 (1.52) | 63.95 (8.56) | 69.70 (13.34) |
| Reaction time | 2.27 (0.63) | 2.31 (0.65) | 2.24 (0.63) |
| Reaction time (fast; s) | 1.86 (0.05) | 1.92 (0.05) | 1.82 (0.04) |
| Reaction time (slow; s) | 2.80 (0.06) | 2.89 (0.07) | 2.80 (0.06) |
| Day 3 (cued and correct on Day 2) | |||
| Hits (%) | 74.32 (1.68) | 65.24 (2.12) | 69.80 (2.52) |
| Dprime | 2.25 (0.11) | 1.78 (0.10) | 2.14 (0.13) |
| Reaction time (s) | 1.98 (0.08) | 2.04 (0.07) | 1.98 (0.07) |
| Day 3 (not cued on Day 2) | |||
| Hits (%) | 46.71 (1.78) | 36.25 (1.80) | 46.16 (2.39) |
| Dprime | 1.16 (0.09) | 0.74 (0.07) | 1.09 (0.09) |
| Reaction time (s) | 2.29 (0.07) | 2.30 (0.08) | 2.31 (0.07) |
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Reaction times relate hits specifically. Data represent means ± SE.
Appendix 1—table 2
Physiological parameters and mood at baseline across Day 1 and Day 3.
| PLAC | YOH | CORT | |||
|---|---|---|---|---|---|
| Day 1 | Heart rate (bpm) | 78.85 (2.67) | 75.97 (2.77) | 76.35 (2.52) | |
| Systolic blood pressure (mmHg) | 107.80 (2.80) | 116.47 (2.63) | 114.66 (3.66) | ||
| Diastolic blood pressure (mmHg) | 68.32 (1.87) | 71.78 (2.18) | 71.00 (2.29) | ||
| cortisol (nmol) | 9.49 (2.02) | 7.16 (1.16) | 10.76 (1.56) | ||
| Mood (good/bad) | 34.80 (0.90) | 33.47 (0.98) | 33.70 (0.87) | ||
| Tiredness (energized/tired) | 31.05 (1.06) | 30.76 (1.14) | 32.30 (1.01) | ||
| Calmity (calm/restless) | 30.50 (1.15) | 30.95 (1.47) | 28.90 (1.07) | ||
| Day 3 | Heart rate (bpm) | 78.65 (2.46) | 78.28 (2.31) | 78.26 (2.38) | |
| Systolic blood pressure (mmHg) | 112.22 (2.14) | 112.42 (3.26) | 114.04 (3.86) | ||
| Diastolic blood pressure (mmHg) | 72.15 (1.48) | 72.66 (1.54) | 68.83 (1.95) | ||
| cortisol (nmol) | 8.41 (1.59) | 5.88 (1.12) | 7.32 (1.01) | ||
| Mood (good/bad) | 34.30 (1.05) | 34.71 (0.81) | 34.10 (0.91) | ||
| Tiredness (energized/tired) | 33.40 (1.05) | 34.09 (0.98) | 32.80 (0.85) | ||
| Calmity (calm/restless) | 30.50 (1.15) | 31.00 (1.20) | 30.90 (1.00) | ||
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Subjective and physiological parameters of participants taken at the beginning of Day 1 and Day 2. There were no significant difference in either subjective or physiological stress parameters between groups. Data represent means (±SE).
Appendix 1—table 3
Significant clusters in the whole-brain analyses of Day 2 memory cueing (correct – incorrect).
| Region | Central coordinates(x, y, z; MNI) | Cluster-P(FWE 0.05) | Cluster-T | |
|---|---|---|---|---|
| Frontal Medial, ACC | –4, 50, –8 | <0.001 | 10.72 | |
| Lateral Occipital L, AG L | −48, –66, 30 | <0.001 | 9.08 | |
| Amygdala L, Striatum L | –14, 4, –16 | <0.001 | 8.22 | |
| Posterior Cingulate Cortex | 4, –41, 38 | <0.001 | 8.10 | |
| Supramarginal Gyrus R | 62, –44, 20 | <0.001 | 7.94 | |
| hippocampus L | −26, –32, –10 | <0.001 | 7.93 | |
| hippocampus R | 32, –40, –12 | <0.001 | 7.89 | |
| Frontal Pole | –22, 38, 42 | <0.001 | 7.32 | |
| Temporooccipital Cortex R | 52, –50, –14 | <0.001 | 6.13 | |
| Superior Parietal R | 30, –46, 62 | <0.001 | 6.11 | |
| Temporooccipital Cortex L | −52, –62, –2 | <0.001 | 6.93 | |
| Postcentral Gyrus | 50, –22, 50 | <0.001 | 5.77 | |
| Superior Frontal Gyrus | –20, 2, 56 | <0.001 | 6.67 | |
| Putamen L | −26,–8, 8 | <0.001 | 6.64 | |
| Mid temporal gyrus L | −62,–16, –8 | <0.001 | 6.37 | |
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Depicted clusters are ordered by cluster-peak T-values.
Appendix 1—table 4
Results from Day 2 gPPI analysis (remembered – forgotten).
| Seed | Target | Cluster size | pFWE (cluster) | pFWE (peak) | |
|---|---|---|---|---|---|
| PCC | Lat. OCC left | 237 | <0.001 | 0.015 | |
| VTC | 1218 | <0.001 | <0.001 | ||
| MPFC | Lat. OCC left | 404 | <0.001 | <0.001 | |
| Sup. Parietal lobe | 836 | <0.001 | <0.001 | ||
| VTC | 1168 | <0.001 | 0.002 | ||
| Left Hippocampus | VTC | 260 | <0.001 | 0.016 | |
| VTC | Lat. OCC left | 789 | <0.001 | <0.001 | |
| Sup. Parietal lobe | 1123 | <0.001 | <0.001 | ||
| VTC | 260 | <0.001 | 0.016 | ||
| PCC | Lat. OCC left | 237 | <0.001 | 0.015 | |
| VTC | 1218 | <0.001 | <0.001 | ||
| MPFC | Lat. OCC left | 404 | <0.001 | <0.001 | |
| Sup. Parietal lobe | 836 | <0.001 | <0.001 | ||
| VTC | 1168 | <0.001 | 0.002 | ||
| Left Hippocampus | VTC | 260 | <0.001 | 0.016 | |
| VTC | Lat. OCC left | 789 | <0.0001 | <0.001 | |
| Sup. Parietal lobe | 1123 | <0.001 | <0.001 | ||
Appendix 1—table 5
Physiological parameters across Day 2.
| PLAC | YOH | CORT | |||
|---|---|---|---|---|---|
| Heart rate (bpm) | Base | 80.42 (2.41) | 75.02 (2.10) | 77.52 (1.97) | |
| Task | 87.40 (2.29) | 81.61 (2.06) | 82.76 (1.86) | ||
| Resting-state post | 80.15 (2.28) | 74.42 (2.21) | 75.28 (2.18) | ||
| +40 | 70.35 (2.58) | 64.92 (2.06) | 67.04 (2.10) | ||
| +55 | 70.65 (2.28) | 65.59 (1.97) | 67.52 (2.33) | ||
| +70 | 69.12 (2.18) | 67.45 (2.37) | 65.61 (2.03) | ||
| +85 | 68.90 (2.40) | 67.47 (1.97) | 65.73 (2.12) | ||
| +100 | 70.25 (2.78) | 69.45 (2.60) | 67.85 (2.16) | ||
| Systolic BP | Base | 113.00 (3.11) | 115.42 (3.11) | 117.95 (3.23) | |
| (mmHg) | +40 | 115.35 (1.95) | 118.00 (3.27) | 117.38 (3.70) | |
| +55 | 110.40 (1.75) | 118.61 (3.36) | 115.83 (3.11) | ||
| +70 | 108.45 (1.71) | 120.92 (3.43) | 115.11 (3.68) | ||
| +85 | 108.50 (2.27) | 122.38 (3.57) | 115.28 (3.34) | ||
| +100 | 107.55 (2.46) | 123.69 (3.29) | 115.78 (3.21) | ||
| Diastolic BP | Base | 72.53 (1.99) | 71.86 (2.61) | 74.57 (2.14) | |
| (mmHg) | +40 | 73.22 (2.26) | 74.14 (1.96) | 73.76 (2.08) | |
| +55 | 72.33 (1.45) | 71.02 (2.10) | 72.67 (2.05) | ||
| +70 | 71.28 (1.64) | 73.31 (2.36) | 72.98 (2.18) | ||
| +85 | 72.85 (1.67) | 75.79 (2.12) | 73.31 (2.30) | ||
| +100 | 71.55 (1.71) | 77.29 (2.30) | 73.98 (1.81) | ||
| cortisol (nmol) | Base | 11.14 (2.14) | 7.22 (1.17) | 8.18 (1.13) | |
| +20 | 5.40 (0.78) | 4.04 (0.39) | 8.15 (2.03) | ||
| +40 | 4.53 (0.62) | 2.92 (0.31) | 24.59 (6.32) | ||
| +70 | 3.63 (0.60) | 3.14 (0.41) | 57.60 (4.88) | ||
| 100 | 2.70 (0.34) | 4.05 (0.69) | 52.93 (4.95) | ||
| Skin conductance | Resting-state pre | 5.82 (1.35) | 3.32 (0.55) | 5.97 (0.86) | |
| Task | 5.88 (1.47) | 3.07 (0.75) | 6.71 (1.31) | ||
| Resting-state post | 9.28 (1.63) | 6.53 (0.96) | 10.02 (1.25) | ||
Appendix 1—table 6
Subjective mood scores across Day 2.
| PLAC | YOH | CORT | ||
|---|---|---|---|---|
| MDBF Base | Mood (good/bad) | 34.85 (1.11) | 34.38 (0.78) | 34.90 (0.72) |
| Tiredness (energized/tired) | 33.85 (1.10) | 33.33 (1.04) | 33.70 (1.03) | |
| Calmness (calm/restless) | 34.85 (1.11) | 34.38 (0.78) | 34.90 (0.72) | |
| MDBF +40 | Mood (good/bad) | 35.05 (1.08) | 34.81 (0.81) | 33.70 (0.81) |
| Tiredness (energized/tired) | 33.70 (0.94) | 33.53 (1.06) | 32.95 (1.01) | |
| Calmness (calm/restless) | 30.55 (0.87) | 28.90 (1.47) | 30.04 (0.91) | |
| MDBF +55 | Mood (good/bad) | 34.70 (0.86) | 35.14 (0.80) | 33.20 (1.09) |
| Tiredness (energized/tired) | 34.10 (0.98) | 33.80 (0.92) | 32.90 (1.10) | |
| Calmness (calm/restless) | 30.00 (0.97) | 30.47 (1.30) | 28.45 (1.75) | |
| MDBF +70 | Mood (good/bad) | 34.55 (1.11) | 34.81 (0.86) | 32.75 (1.07) |
| Tiredness (energized/tired) | 33.65 (1.08) | 34.28 (1.08) | 32.75 (1.16) | |
| Calmness (calm/restless) | 29.55 (1.43) | 30.81 (1.34) | 29.60 (1.38) | |
| MDBF +85 | Mood (good/bad) | 34.20 (1.14) | 34.09 (0.93) | 32.30 (1.20) |
| Tiredness (energized/tired) | 33.20 (1.18) | 33.47 (1.23) | 31.60 (1.14) | |
| Calmness (calm/restless) | 28.80 (1.73) | 30.71 (1.56) | 28.55 (1.58) | |
| MDBF +100 | Mood (good/bad) | 33.30 (1.39) | 33.19 (1.16) | 32.55 (1.02) |
| Tiredness (energized/tired) | 32.70 (1.34) | 32.61 (1.38) | 32.50 (1.26) | |
| Calmness (calm/restless) | 30.20 (1.36) | 29.19 (1.56) | 29.40 (1.48) |
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Subjective mood ratings according to the Mehrdimensionale Befindlichkeitsfragebogen (MDBF Katsuki et al., 1997) across Day 2. Scores did not reveal a significant difference in either scale between groups. Data represent means (±SE).
Appendix 1—table 7
Participants’ state, trait anxiety, chronic stress, and depression scores.
| PLAC | YOH | CORT | |
|---|---|---|---|
| Depression score | 6.20 (0.89) | 9.04 (1.20) | 7.47 (1.00) |
| State anxiety | 43.20 (1.02) | 42.09 (0.94) | 42.38 (1.16) |
| Trait anxiety | 43.05 (1.41) | 46.95 (1.79) | 45.19 (0.93) |
| Chronic stress | 70.95 (6.86) | 90.61 (8.42) | 77.14 (5.37) |
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State and Trait anxiety scores were measured with the State-Trait Anxiety Inventory. Depression Scores were determined utilizing the Beck Depression Inventory. Chronic stress was measured with the Trier Inventory of Chronic Stress. Participants conducted the three questionnaires at home before the actual experiment started. Data represent means (±SE).
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Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation
eLife 13:RP100525.
https://doi.org/10.7554/eLife.100525.3
