Research reportPsychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat
Introduction
Corticotropin-releasing hormone (CRH) is a 41 amino acid neuropeptide that acts in discrete but widespread areas of the brain to coordinate physiological and behavioral responses to threatening situations 3, 31, 44. CRH pathways emanating from the paraventricular nucleus of the hypothalamus (PVN) activate the pituitary–adrenal axis and sympathetic nervous system while inhibiting so-called vegetative functions whose inhibition is adaptive during stress (e.g., feeding, sexual behavior, growth, reproduction) 6, 9. On the other hand, a growing body of evidence suggests that activation of CRH receptors in the central nucleus of the amygdala (CEA) and/or CRH pathways emanating from the CEA play an important role in the fear-related behaviors. Electrical lesions of the CEA, but not of the PVN, abolished many of the behavioral effects of centrally administered CRH such as conditioned startle [24], whereas chemical lesion of the CEA blocked fear-potentiated startle [23]. The direct injection of CRH antagonist into the CEA also diminished the stress-evoked freezing [41]or reduced emotionality in socially defeated rats [13].
Although both hypothalamic and amygdala-derived CRH are thought to interact in the activation of brainstem arousal centers such as the locus coeruleus (LC) [10], they do not necessarily respond in a similar fashion to the same stimuli. We and others have previously reported that while sustained glucocorticoid administration inhibits the hypothalamic CRH system, it causes a subtle but significant increase in the levels of CRH mRNA in the amygdala 26, 40, 43. On the other hand, although restraint or footshock stress which gives both physical and psychological threats to the rats have been shown to activate the hypothalamic CRH system 43, 44, evidence for the activation of amygdala CRH system under these mixed stressors is still limited. Thus, while two other groups demonstrated activation of the amygdala CRH system following mild restraint stress 15, 19, 35, we have shown that immobilization stress that increases PVN CRH mRNA fails to increase CRH mRNA levels in the CEA [32].
In contrast, whether the PVN and amygdala CRH systems are differentially responsive to psychological stressors has not yet been determined. Given the fact that the amygdala CRH system seems to play a preferential role in fear-related behaviors, we sought to test whether the amygdala CRH system was more sensitive than the hypothalamic CRH system to a psychological stressor. To test the impact of well characterized psychological stressor on the hypothalamic CRH system, we assessed CRH mRNA levels and content in the PVN, CRH content in the median eminence (ME), and the secretion of plasma ACTH and corticosterone (CORT). In the amygdala, we measured CRH mRNA and content in the CEA, as well as the bed nucleus of the stria terminalis (BNST), thought to represent extended amygdala. CRH content in the LC was also measured, because it has been suggested that the LC is one of the important target areas of CRH neurons emanating from the CEA 21, 42. In addition, as an index of tissue-specific effects of CRH, we measured mRNA levels of type-1 CRH receptor (CRHR-1) in the PVN, amygdala and BNST 16, 28.
Section snippets
Materials and methods
Male Wistar rats, weighing 250–280 g, were individually housed under conditions of controlled temperature and illumination (0800–2000 h) and were allowed ad libitum access to food and water.
Plasma CORT and ACTH responses to psychological stress
As shown in Table 1, plasma CORT and ACTH were unaltered at both 1.5 and 3 h following psychological stress. This is consistent with a previous report [38]demonstrating that psychological stress identical in the present study did not evoke robust pituitary–adrenocortical responses.
CRH mRNA changes in the PVN, CEA and BNST
Consistent with plasma ACTH and CORT responses, CRH mRNA in the PVN did not show any significant changes following psychological stress (Fig. 1Fig. 2). In contrast, CRH mRNA in the CEA significantly increased at both
Discussion
We report here that CRH mRNA and content are both increased in the CEA following the psychological stress generated in the communication box. Psychological stress also increased CRH mRNA in the dorsolateral subdivision of the BNST, whereas CRH content in that region showed a tendency towards an increase. In contrast, we found that psychological stress failed to elevate any components of the hypothalamic–pituitary–adrenocortical (HPA) axis (i.e., CRH mRNA and content in the PVN, CRH content in
Acknowledgements
We are extremely grateful to Dr. K. Mayo and Dr. W. Vale for providing the ribonucleotide probes for CRH and CRHR-1. We also wish to thank Drs. K. Asaba and M. Nishiyama for plasma CORT measurement, and Miss M. Nakatsukasa for her technical assistance.
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