Elsevier

NeuroImage

Volume 32, Issue 3, September 2006, Pages 1290-1298
NeuroImage

Influence of the stress hormone cortisol on fear conditioning in humans: Evidence for sex differences in the response of the prefrontal cortex

https://doi.org/10.1016/j.neuroimage.2006.05.046Get rights and content

Abstract

The stress hormone cortisol is known to influence declarative memory and associative learning. In animals, stress has often been reported to have opposing effects on memory and learning in males and females. In humans, the effects of cortisol have mainly been studied at the behavioral level. The aim of the present experiment was to characterize the effects of a single cortisol dose (30 mg) on the hemodynamic correlates of fear conditioning. In a double-blind group comparison study subjects (17 females and 17 males) received 30 mg cortisol or placebo orally before participating in a discriminative fear conditioning paradigm. Results revealed that cortisol impaired electrodermal signs of learning (the first interval response) in males, while no conditioned SCRs emerged for the females independent of treatment. fMRI results showed that cortisol reduced activity for the CS+ > CS− comparison in the anterior cingulate, the lateral orbitofrontal cortex and the medial prefrontal cortex in males. Opposite findings (increase in these regions under cortisol) were detected in females. In addition, cortisol reduced the habituation in the CS+ > CS− contrast in the dorsolateral prefrontal cortex independent of sex. Finally, cortisol also modified the response to the electric shock (the UCS) by enhancing the activity of the anterior as well as the posterior cingulate. In sum, these findings demonstrate that in humans cortisol mostly influences prefrontal brain activation during fear conditioning and that these effects appear to be modulated by sex.

Introduction

Exposure to stress influences cognition in animals and humans. It has been demonstrated that stress-induced activation of the hypothalamus–pituitary–adrenal (HPA) axis and the subsequent release of glucocorticoids (GCs; corticosterone in rats, cortisol in humans) is amongst other factors such as epinephrine or corticotropin-releasing hormone (CRH) responsible for this effect. Various studies have investigated the effects of stress hormones on hippocampal mediated declarative or explicit memory. Animal as well as human studies have frequently observed that stress or cortisol treatment impairs delayed memory retrieval, while enhancing memory consolidation (for recent reviews, see Het et al., 2005, Lupien et al., 2005, Roozendaal, 2002, Wolf, 2003). Animal studies have demonstrated that the amygdala interacts with the hippocampus in mediating both of these effects (Roozendaal, 2002). Negative effects on retrieval are associated with reduced regional cerebral blood flow in the medial temporal lobe as demonstrated in a PET study (de Quervain et al., 2003, Roozendaal, 2002). In line with this observation, a resting state FDG PET study observed reduced hippocampal glucose uptake after cortisol treatment (de Leon et al., 1997). Recent studies in humans have suggested that cortisol especially enhances the consolidation of emotional memory, which suggests a specific effect of the hormone on amygdala function (Buchanan and Lovallo, 2001, Cahill et al., 2003). In support of this hypothesis, a positive correlation between cortisol levels and amygdala activity has been observed in a PET study with depressed patients (Drevets et al., 2002).

In rodents, multiple experiments have investigated the effects of stress on associative learning. Acute stress for example has been found to enhance delay as well as trace eye-blink conditioning in male rats, yet impair it in female rats (Shors, 2004). Similarly striking sex differences have also been observed for spatial memory tasks, even though here male rats show a stress-induced impairment, while female rats show a stress-induced enhancement (Conrad et al., 2004, Luine, 2002). With respect to the amygdala, mediated forms of memory enhanced fear conditioning as well as enhanced avoidance learning have been observed after acute or chronic stress as well as pharmacological GC treatment (Bohus and Lissak, 1968, Conrad et al., 1999, Corodimas et al., 1994, Flood et al., 1978, Hui et al., 2004, Zorawski and Killcross, 2002). These results have been interpreted as indicating enhanced amygdala but reduced hippocampal functioning in times of high cortisol levels (Sapolsky, 2003). In humans, observations of an association between endogenous cortisol levels and galvanic skin responses in fear conditioning paradigms have only recently been reported for the first time. Interestingly, both studies reported that basal (Zorawski et al., 2005) or stress-induced (Jackson et al., 2006) cortisol levels were associated with changes in conditioning in males but not in females, again pinpointing towards substantial sex differences.

In humans and primates, a large number of glucocorticoid receptors are present in the prefrontal cortex, which suggests that these regions are major targets of cortisol action in humans (Lupien and Lepage, 2001). In line with these observations, several studies reported that working memory, which is mediated by prefrontal regions, is impaired after stress or cortisol treatment (Elzinga and Roelofs, 2005, Lupien et al., 1999, Lyons et al., 2000, Wolf et al., 2001a, Wolf et al., 2001b). Vice versa, the anterior cingulate gyrus has been implicated in the modulation of the hypothalamus–pituitary–adrenal axis in rodents and humans (Diorio et al., 1993, Wolf et al., 2002). This region and other prefrontal regions inhibit amygdala and HPA responses to stress (Amat et al., 2005). Hariri et al. (2003) further report an inverse correlation of prefrontal cortex and amygdala activation in reaction to fear-related stimuli. A recent perfusion fMRI study reported that activity in the right PFC and the anterior cingulate was associated with stress-induced changes in cortisol secretion (Wang et al., 2005). These correlative fMRI findings indicate together with experimental lesion work in animals (e.g., Diorio et al., 1993) the involvement of prefrontal brain regions in the regulation of the (HPA) stress response in humans.

Thus, several structures involved in emotional learning are influenced by cortisol and stress. Fear conditioning is a well-established method to study emotional associative learning processes. Lesion studies as well as functional imaging studies with humans identified the amygdala and prefrontal structures (e.g., anterior cingulate and orbitofrontal cortex) as crucial for the acquisition and expression of fear. Human patients with amygdala damage showed impaired fear conditioning when measuring skin conductance responses and startle response (Bechara et al., 1995, LaBar et al., 1995, Weike et al., 2005). An increasing number of functional fear conditioning studies confirmed the involvement of these structures in healthy humans but also considered a more widespread network including the sensory and insular cortex, the hypothalamus, the thalamus, and the hippocampus (LaBar et al., 1998, Tabbert et al., 2005, Büchel et al., 1999, Knight et al., 1999, Knight et al., 2004a, Knight et al., 2004b, Fischer et al., 2000, Bradley et al., 2003). A variety of stimuli (e.g., human faces or colored lights) and conditioning paradigms (e.g., differential vs. simple conditioning, delay vs. trace conditioning) have thereby been employed, altering the constellation of the structures involved. Regarding the influence of stress-related substances on emotional learning, previous human neuroimaging studies have investigated the influence of the modulation of the adrenergic system on emotional declarative memory formation (Strange and Dolan, 2004, van Stegeren et al., 2005). However, to the best of our knowledge, no human imaging study has so far investigated the effects of the stress hormone cortisol on fear conditioning. The aim of the present experiment was therefore to investigate the effects of cortisol on the patterns of cerebral activation in healthy young subjects exposed to a fear conditioning paradigm. Given the substantial animal literature on sex differences (see above), we were additionally interested in characterizing potential differences between female and male participants.

In detail, we applied a differential conditioning paradigm in which two former neutral visual stimuli served as conditioned stimuli and an electric shock as an unconditioned stimulus (UCS). One of the conditioned stimuli (CS+) always announced the UCS, while the other conditioned stimulus (CS−) was never followed by the UCS. We measured central blood oxygenation level-dependent (BOLD) responses via functional magnetic resonance imaging, as well as autonomic electrodermal responses. We hypothesized that cortisol treatment would affect the learning process at least regarding the following two aspects: first, cortisol can enlarge or diminish the response differences to CS+ and CS−. Secondly, treatment can affect the habituation rates to CS+ and CS−. Büchel et al. (1998) demonstrated for amygdala responses that habituation slopes are a useful measure of conditioning effects. We also examined the cortisol effect on the responses towards the UCS. If a treatment effect on learning indeed occurs, it might well be possible that reactions to the UCS are modulated, as the functional value of associative learning is to prepare the organism to effectively deal with an UCS as Domjan (2005) recently pointed out.

Section snippets

Subjects

A total of 34 subjects (17 female) participated in the study, which was approved by the ethics committee of the German Psychological Society. Corresponding to the experimental design, we divided the sample into four groups: female placebo group (n = 9), female cortisol group (n = 8), male placebo group (n = 8), and male cortisol group (n = 9). The mean age of the entire sample was 24.2 years (SD = 7.5) with no significant differences between the four groups with respect to age. Most of the

Cortisol levels

Cortisol levels of the four groups did not differ at baseline. In response to cortisol administration, all subjects showed pronounced increases of 90 nmol/l and larger. Some subjects displayed extremely high cortisol levels 15 min after cortisol intake (larger than 1000 nmol/l), which most likely reflects some micro residue of the uncoated tablet in the mouth of the participants. In the placebo groups, none of the participants showed elevated cortisol levels. In fact a moderate decrease typical

Discussion

The present study was designed to examine the neural correlates of the influence of the stress hormone cortisol on fear conditioning. Concerning the fear conditioning process, we were interested in the effects of cortisol on the learned differentiation between CS+ and CS− and the time course of this differentiation. We further asked whether the hemodynamic responses to the electric shock were altered by cortisol.

Before focusing on the treatment effects, we would like to shortly discuss the

References (71)

  • S. Het et al.

    A meta-analytic review of the effects of acute cortisol administration on human memory

    Psychoneuroendocrinology

    (2005)
  • G.K. Hui et al.

    Memory enhancement of classical fear conditioning by post-training injections of corticosterone in rats

    Neurobiol. Learn. Mem.

    (2004)
  • E.D. Jackson et al.

    Stress differentially modulates fear conditioning in healthy men and women

    Biol. Psychiatry.

    (2006)
  • M.L. Kringelbach et al.

    The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology

    Prog. Neurobiol.

    (2004)
  • S. Kuhlmann et al.

    Effects of oral cortisol treatment in healthy young women on memory retrieval of negative and neutral words

    Neurobiol. Learn. Mem.

    (2005)
  • K.S. LaBar et al.

    Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study

    Neuron

    (1998)
  • S.J. Lupien et al.

    Stress, memory, and the hippocampus: can't live with it, can't live without it

    Behav. Brain Res.

    (2001)
  • S.J. Lupien et al.

    Glucocorticoids: effects on human cognition

  • R.C. Oldfield

    The assessment and analysis of handedness: the Edinburgh inventory

    Neuropsychologia

    (1971)
  • K.L. Phan et al.

    Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI

    NeuroImage

    (2002)
  • C.R. Pryce et al.

    Effect of sex on fear conditioning is similar for context and discrete CS in Wistar, Lewis and Fischer rat strains

    Pharmacol. Biochem. Behav.

    (1999)
  • B. Roozendaal

    Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval

    Neurobiol. Learn. Mem.

    (2002)
  • K. Tabbert et al.

    Hemodynamic responses of the amygdala, the orbitofrontal cortex and the visual cortex during a fear conditioning paradigm

    Int. J. Psychophysiol.

    (2005)
  • A.H. van Stegeren et al.

    Noradrenaline mediates amygdala activation in men and women during encoding of emotional material

    NeuroImage

    (2005)
  • O.T. Wolf

    HPA axis and memory

    Best Pract. Res. Clin. Endocrinol. Metab.

    (2003)
  • O.T. Wolf et al.

    The relationship between stress induced cortisol levels and memory differs between men and women

    Psychoneuroendocrinology

    (2001)
  • M. Zorawski et al.

    Posttraining glucocorticoid receptor agonist enhances memory in appetitive and aversive Pavlovian discrete-cue conditioning paradigms

    Neurobiol. Learn. Mem.

    (2002)
  • J. Amat et al.

    Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

    Nat. Neurosci.

    (2005)
  • A. Bechara et al.

    Decision making and impulse control after frontal lobe injuries

    Curr. Opin. Neurol.

    (2005)
  • A. Bechara et al.

    Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans

    Science

    (1995)
  • M.M. Bradley et al.

    Activation of the visual cortex in motivated attention

    Behav. Neurosci.

    (2003)
  • B. Bromm

    Brain images of pain

    News Physiol. Sci.

    (2001)
  • C. Büchel et al.

    Amygdala–hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging

    J. Neurosci.

    (1999)
  • L. Cahill

    Sex-related influences on the neurobiology of emotionally influenced memory

    Ann. N. Y. Acad. Sci.

    (2003)
  • L. Cahill et al.

    Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding

    Learn. Mem.

    (2003)
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