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