Neural mechanisms of noradrenaline and cortisol effects on memory accuracy vs. generalization over time

During a stressful experience, noradrenaline and cortisol interact to induce
strong and lasting memories. However, the role of these stress mediators in
modifying the quality of these memories is still unclear. According to the
memory transformation hypothesis, memories become less accurate over time as
they are being transformed from contextually detailed, hippocampus-dependent
memories to more gist-like, neocortical representations. Rodent studies
suggests that noradrenaline and cortisol differentially modulate this memory
transformation process. Whereas noradrenaline was shown to maintain long-term
memory accuracy and hippocampus dependency, cortisol contributed to early
memory generalisation, suggesting that stressful memories become independent
from the hippocampus more rapidly. We developed a new paradigm to investigate
memory quality in humans and hypothesize that increases in noradrenaline during
learning maintain long-term memory accuracy and hippocampus dependency, whereas
enhanced cortisol levels promote memory generalization and a more rapid
transformation of the memory trace to neocortical structures.

The aim of this experiment is to determine the differential effects of
noradrenaline and cortisol on memory accuracy versus generalization and to
investigate the divergent effects of these stress mediators on the neural
mechanisms underlying the reorganisation of detailed into gist-like memories
over time.

This experiment is a double-blind placebo controlled between subject
intervention study.

The study includes 4 different groups: 40mg atomoxetine + placebo, 20mg
hydrocortisone + placebo, 40mg atomoxetine + 20mg hydrocortisone, 2 placebo
tablets. Within each group, both tablets are taken once at the beginning of the
experiment (atomoxetine ~120min before the MRI task, hydrocortisone ~60min
before the MRI task).

We estimate the burden and risks of this study as negligible.
Subjects participate in two experimental sessions which are 28 days apart. Both
sessions consist of questionnaires, cognitive tasks and physiological
measurements (skin conductivity, pupil dilation, heart rate, respiration). All
tasks and the structural and resting state scans take place inside a 3T MRI
scanner (2 scan sessions à 1.5h). Loud noise in the scanner and lying in a
small confined space may lead to discomfort in some participants. During
session 1, participants receive an oral administration of atomoxetine,
hydrocortisone or both or placebo. Both atomoxetine and hydrocortisone do not
have a potential for abuse, they have a relatively short half-life and rapid
clearance which minimizes accumulation of the drugs, and they have no known
interaction effects. Therefore, these drugs have a very favourable safety
profile and a high tolerability. Only a single and relatively low dose of the
drugs is administered similar to other experimental studies that use
atomoxetine and hydrocortisone as challenge agents (none of which reported any
adverse events or side effects). During both sessions, participants perform a
virtual environment task, which has been optimized to prevent
navigation-induced motion sickness. During session 1, participants perform a
differential fear conditioning task that is embedded in the virtual
environment. In this task, participants sometimes receive mild electric shocks
to evoke a fear response. This procedure has been widely used in humans in
classical aversive conditioning paradigms.