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Randomized Controlled Trial
. 2023 Oct 25;43(43):7198-7212.
doi: 10.1523/JNEUROSCI.0916-23.2023. Epub 2023 Oct 9.

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements

Brynn E Sherman  1 , Bailey B Harris  2 , Nicholas B Turk-Browne  3   4 , Rajita Sinha  5 , Elizabeth V Goldfarb  6   4   5   7
Affiliations
Randomized Controlled Trial

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements

Brynn E Sherman et al. J Neurosci. .

Abstract

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.

Keywords: associative memory; cortisol; emotional memory; fMRI; functional connectivity; stress.

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Figures

Figure 1.
Figure 1.
Task design and cortisol assays. A, Participants completed the experimental procedure twice (on two separate weeks; order counterbalanced across participants). They first received a pill containing either 20 mg hydrocortisone or no active substance (placebo). They then completed a memory encoding task while undergoing fMRI. The encoding task consisted of two runs of encoding object-scene pair associations. Objects were either neutral (handheld objects) or emotional (alcoholic beverages; order counterbalanced across participants). Each encoding run took ∼9 min. Participants returned 24 h later to be tested on their memory for individual objects (Object Recognition Test; 7.5 min) and object-scene associations (Associative Memory Test; 7 min). B, During encoding, participants viewed an object-scene pair for 5 s, during which they imagined the object and scene interacting. They then rated whether the imagined interaction made them feel happy, neutral, or unhappy (valence) and how intensely they felt that way (arousal). C, During the associative memory task, participants were shown an object and asked to identify its associated scene. The options included the correct scene, a perceptually matched lure scene, another scene (which had been encoded with a different object), and a perceptually matched lure for the incorrect scene. Choosing the correct scene denotes correct associative memory. D, Participants provided three saliva samples throughout the encoding session: before pill administration (after a 10 min acclimation period), before encoding (∼1 h post-pill), and after encoding (∼2 h post-pill). They also completed the PANAS and provided a guess as to which pill they received, both before and after the scanning sessions. E, Hydrocortisone led to elevated salivary cortisol concentrations at the two post-pill administration time points, indicating that cortisol was elevated during memory encoding. Small dots represent individual participants. Larger diamonds represent mean across participants.
Figure 2.
Figure 2.
Behavioral results. A, Participants rated emotional associations as more arousing than neutral associations. B, Cortisol altered the valence of encoded associations, such that participants were less likely to endorse feeling “neutral” about the object-scene pair. C, Participants performed above chance (0.25; dashed line) on the associative memory test, with better memory for neutral associations. D, Cortisol altered the relationship between arousal and memory. Participants with high subjective arousal had better associative memories under cortisol, but worse memories under placebo. E, The cortisol-induced change in happiness ratings predicted associative memory, such that participants with greater increases in happiness had better memory. A–C, Small dots represent individual participants. Larger diamonds represent mean across participants. D, E, Each dot represents an individual participant. Error shading represents 95% CI around the line of best fit, collapsed across blocks (black line). Individual colored lines indicate the line of best fit within each block. *p < 0.05. **p < 0.01.
Figure 3.
Figure 3.
Background connectivity results. A, Left, Example hippocampal and medial temporal lobe subfields on a representative participant. Right, Schematic of hippocampal trisynaptic pathway. B, Hydrocortisone led to increased background connectivity between hippocampal subregions. C, CA1-CA23DG connectivity interacted with pill and block to predict associative memory. D, CA1-CA23DG connectivity interacted with pill to predict subjective arousal. E, The cortisol-induced increase in happiness ratings as a function of the cortisol-induced increase in CA1-CA23DG connectivity. B, Small dots represent individual participants. Larger diamonds represent mean across participants. *p < 0.05. C–E, Error shading represents 95% CI around the best fit line.
Figure 4.
Figure 4.
Within-run pattern similarity results. A, We extracted the spatiotemporal pattern associated with each encoding trial. We then correlated each trial to all other trials (averaging the correlations across trials) to obtain a global pattern similarity metric. B, CA23DG pattern similarity differed by block, with relatively greater neural similarity among emotional associations. C, CA23DG pattern similarity predicted subsequent associative memory in opposing directions under cortisol versus placebo. D, The difference in CA23DG similarity from cortisol to placebo positively predicted the cortisol-induced increase in happiness ratings from emotional, but not neutral associations. B, Small dots represent individual participants. Larger diamonds represent mean across participants. *p < 0.05. C, D, Error shading represents 95% CI around the best fit line. Individual colored lines indicate the line of best fit within each block.
Figure 5.
Figure 5.
Hippocampal subsequent memory effects. A, Univariate subsequent memory effect (difference in encoding activation for subsequently remembered, vs forgotten trials), averaged across all voxels in the hippocampus. B, Subsequent memory effect in CA23DG. C, Subsequent memory effect in CA1. Small dots represent individual participants. Larger diamonds represent mean across participants. *p < 0.05.
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