Research report
Corticosterone facilitates retention of contextually conditioned fear and increases CRH mRNA expression in the amygdala

https://doi.org/10.1016/S0166-4328(03)00216-XGet rights and content

Abstract

The present study examined the effects of glucocorticoid administration on emotional memory and on corticotropin-releasing hormone (CRH) mRNA expression in the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN). This was tested by administering repeated corticosterone (CORT) within a contextual fear conditioning paradigm. Rats received 2.5 mg/kg (s.c.) CORT or placebo twice a day for five and a half days and, 2 h after the last injection, rats were given one-trial contextual fear conditioning. When tested for retention of conditioned fear 6 days later, the CORT-treated rats displayed more fear-conditioned freezing in the retention test than vehicle-treated rats, which was not accounted for by an increase in footshock responsivity nor elevated plasma CORT. Another group of rats was fear conditioned prior to CORT administration, followed 24 h later by the five and a half days of CORT, and tested 6 days later; conditioned fear was not enhanced in these rats. Finally, CORT administration produced an increase of CRH mRNA in the CeA and a decrease in the PVN. The data suggest that repeated administration of CORT given before fear conditioning facilitates the acquisition of emotional memory, whereas CORT given after consolidation does not increase emotional memory.

Introduction

Neuroendocrine mechanisms are known to sustain states of fear [19], [20]; glucocorticoids are elevated during these states in order to allow physiological and cognitive responses to the stress- and fear-inducing situations [25], [31]. Repeated glucocorticoid administration increases tonic immobility in domestic fowls [18] and facilitates corticotropin-releasing hormone (CRH)-potentiated acoustic startle [24] and freezing behavior in rats to a cue-specific fear stimulus [10]. Glucocorticoids are necessary to sustain fear-related responses, to facilitate appraisal of events, and to development [45] and consolidation [38] of fear. Within contextual fear conditioning paradigms, glucocorticoid antagonists impair the acquisition of conditioned fear [9], [37]. Administration of low to moderate doses of exogenous glucocorticoids enhance aversive conditioning and facilitate extinction of active avoidance [22], [39] while high doses can impair aversive conditioning and delay extinction [22].

When glucocorticoid concentrations increase, occupation of glucocorticoid receptors may influence perceptual detection thresholds to aid in focused attention on the perceived stimulus, to the exclusion of irrelevant stimuli [16]. At the cellular level, glucocorticoids exert fast rapid membrane-related effects and genomic actions through transcription of mRNAs. These cellular effects are important for the regulation of numerous genes including neuropeptides such as CRH [26], [44]. Chronic glucocorticoid administration increases CRH mRNA expression in the central nucleus of the amygdala. The central nucleus of the amygdala has also been linked to the enhanced behavioral effects of CRH on fear or anxiety-related measures in rats [21], [23]. Moreover, chronic glucocorticoids implanted into the amygdala increased CRH mRNA in CeA and decreased exploration in the elevated plus maze suggesting increased anxiety [43]. Corodimas et al. [10] reported that corticosterone (CORT) administered for 5 days following cue-specific conditioning increased freezing when animals were exposed to the conditioned stimulus on the fifth day of administration. In addition, Cordero et al. [9] found corticosterone administration immediately following training facilitated retention of context fear. Thus, corticosterone administration facilitated conditioned fear to an explicit conditioned auditory and contextual cues. These facilitatory effects of chronic glucocorticoid administration on aversively motivated behavior are thought to be a consequence of the increased expression of CRH in the amygdala [26], [27], [43], [44], [47], [48].

The present study was designed to test whether chronic CORT present at the time of training facilitates contextual fear conditioning and whether chronic CORT given 24 h after training facilitates retention. Rats were given repeated CORT or vehicle administration prior to initial conditioning and tested for retention on the sixth day following conditioning. Another group was conditioned first, given repeated CORT or vehicle administration begun 1 day following training, and then tested for retention 6 days after the last CORT injection. CRH mRNA was measured in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) following repeated corticosterone administration to demonstrate the effect of chronic CORT administration. We hypothesize that if repeated CORT administration potentiates amygdala function, then contextual fear conditioning should be facilitated. Additionally, if CORT facilitates fear conditioning via time-dependent learning and memory processes [32], administration of CORT beginning 1 day following conditioning, which is outside of the consolidation window, should not affect retention of learned fear.

Section snippets

Animals

Male Sprague–Dawley rats from Harlan (Indianapolis, IN) weighing between 250 and 350 g were individually housed with a 12 h/12 h light/dark cycle and given ad libitum access to food and water. Animals were handled daily by the experimenter for 2–3 days prior to the beginning of each experiment. The University of Delaware’s Institutional Animal Care and Use Committee approved all experimental procedures.

Apparatus

The same chambers were used for fear conditioning and memory retention testing. Each chamber

Effects of CORT on fear conditioning

When rats were given five and a half days of CORT injections before fear conditioning, there was no difference in post-shock freezing between the vehicle (mean±S.E.M. percent freezing=50.3±4.9) and CORT (56.2±4.6) groups. Rats in the vehicle group froze about 50% of the post-shock period time, but then froze less during the retention test 6 days later (28.8±4.0). This indicates that there is memory for contextual fear conditioning 6 days after training but the levels of freezing are diminished

Discussion

The results indicate that repeated pre-training injections of CORT facilitate the memory of learned fear. The facilitation occurred when plasma corticosterone and CRH mRNA in the CEA were elevated at the time of training. The same repeated CORT administration regimen begun 24 h following fear conditioning had no effect on retention. These data suggest elevated plasma CORT and CRH in the amygdala enhance associative learning processes to increase retention of fear. Furthermore, our data are

Acknowledgements

This research was supported by the NSF Grant #IBN-0129809 and NIDA Grant #1 RO3 DA12607-01 awarded to J.B.R.

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