The role of the posterior medial bed nucleus of the stria terminalis in modulating hypothalamic–pituitary–adrenocortical axis responsiveness to acute and chronic stress

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Summary

The bed nucleus of the stria terminalis (BST) plays a prominent role in brain integration of acute responses to stressful stimuli. This study tests the hypothesis that the BST plays a complementary role in regulation of physiological changes associated with chronic stress exposure. Male Sprague-Dawley rats received bilateral ibotenate lesions or sham lesions of the posterior medial region of the BST (BSTpm), an area known to be involved in inhibition of HPA axis responses to acute stress. Chronic stress was induced by 14-day exposure to twice daily stressors in an unpredictable sequence (chronic variable stress, CVS). In the morning after the end of CVS, stressed and non-stressed controls were exposed to a novel restraint stress challenge. As previously documented, CVS caused adrenal hypertrophy, thymic involution, and attenuated body weight gain. None of these endpoints were affected by BSTpm lesions. Chronic stress exposure facilitated plasma corticosterone responses to the novel restraint stress and elevated CRH mRNA. Lesions of the BSTpm increased novel stressor-induced plasma ACTH and corticosterone secretion and enhanced c-fos mRNA induction in the paraventricular nucleus of the hypothalamus (PVN). In addition, lesion of the BSTpm resulted in an additive increase in CVS-induced facilitation of corticosterone responses and PVN CRH expression. Collectively these data confirm that the BSTpm markedly inhibits HPA responses to acute stress, but do not strongly support an additional role for this region in limiting HPA axis responses to chronic drive. The data further suggest that acute versus chronic stress integration are subserved by different brain circuitry.

Introduction

Activation of the hypothalamic–pituitary–adrenal (HPA) axis is a critical component of the body's stress response. The main output of this axis is the release of glucocorticoids from the adrenal cortex into the circulation, primarily to redistribute energy resources following a real or perceived threat to homeostasis (McEwen and Stellar, 1993). The release of glucocorticoids from the adrenal glands is stimulated by circulating adrenocorticotropic hormone (ACTH) released from the anterior pituitary. Upstream, ACTH release is driven by hypophysiotrophic secretagogues, including corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), which are synthesized and released by neurons in the paraventricular nucleus (PVN) of the hypothalamus.

During chronic stress, prolonged or repeated activation of the HPA axis can lead to long-term changes in HPA tone and responsiveness. In particular, chronic stress can lead to potentiated basal ACTH and/or corticosterone secretion, adrenal hypertrophy, and elevated PVN CRH and AVP mRNA and protein expression (Hauger et al., 1988; Herman et al., 1995; Kiss and Aguilera, 1993; Ulrich-Lai et al., 2006b). Chronic exposure to homotypic stressors typically engender some degree of HPA axis habituation (Dhabhar et al., 1997; Odio and Brodish, 1989; Pitman et al., 1988; Viau and Sawchenko, 2002). However, despite the presence of an enhanced glucocorticoid feedback signals, HPA responses to new stressors are either maintained or augmented following chronic stress a process known as stress facilitation (Armario et al., 1985; Bhatnagar and Dallman, 1998; Bhatnagar and Vining, 2003; Dallman et al., 1992; Hauger et al., 1990; Kiss and Aguilera, 1993; Ostrander et al., 2006). Additionally, chronic stress is implicated in the dysregulation of glucocorticoid secretion that is associated with many disease states such as depression, post-traumatic stress disorder (PTSD) and other anxiety disorders (see Gold and Chrousos, 2002).

There is considerable evidence indicating that HPA axis reactivity to stress is influenced by a number of limbic forebrain regions, including the amygdala, hippocampus, and prefrontal cortex (see Herman et al., 2005). These limbic regions have little direct input to the medial parvocellular PVN and most likely modulate the release of CRH and AVP through synaptic relay circuits. Anatomical studies indicate that the hippocampus and amygdala mainly relay signals by heavily innervating PVN-projecting basal forebrain and hypothalamic structures. Notably, the bed nucleus of the stria terminalis (BST) is among the main extrahypothalamic regions that receives abundant input from all of the noted limbic regions (Cullinan et al., 1993; Dong et al., 2001b; Dong and Swanson, 2004; Gu et al., 2003; Sawchenko and Swanson, 1983).

Several lines of evidence mark the BST as a major mediator of the HPA axis responses to stress (Casada and Dafny, 1991; Crane et al., 2003; Dunn, 1987; Feldman et al., 1990; Forray and Gysling, 2004; Gray et al., 1993; Zhu et al., 2001) raising the possibility that the BST may play a role in HPA axis disorders mediated by upstream limbic structures. The BST can be subdivided into a number of cytoarchitecturally distinct subnuclei with distinct afferent input and efferent targets (Swanson, 1998). In particular, the posterior medial area of the BST (BSTpm) which includes the principal nucleus is known to be a major inhibitor of neuroendocrine responses to acute stress (Choi et al., 2007; Dunn, 1987; Herman et al., 1994). However, the role of the BSTpm in chronic stress regulation remains to be determined and may provide further understanding of how adaptations in limbic BST circuitry may play a role in stress-related disease states. Since our previous work had demonstrated strong inhibition of acute HPA responses by the BSTpm (Choi et al., 2007), the current studies test the hypothesis that the BSTpm is necessary for regulating neuroendocrine and physiological responses to chronic stress. To test this hypothesis, this study uses bilateral ibotenate lesions targeting the PVN-projecting BSTpm to assess the necessity of this region for mediating central and peripheral HPA axis responses to 14 days of chronic variable stress (CVS).

Section snippets

Animals

Forty-eight adult male Sprague Dawley rats (275–300 g Harlan, Indianapolis, IN) were used for this study. All rats were housed three per cage in conventional shoebox rat cages. Food and water were available ad libitum in a temperature and humidity controlled vivarium, maintained on a 12/12-h light/dark cycle (lights on at 0600 h). Upon arrival, all rats acclimated to the animal facility for at least 7 days prior to surgery. Animals were maintained in accordance with the Guide for the Care and Use

Verification of lesions of the posterior medial BST

Bilateral ibotenate lesions targeted the principal nucleus of the BST. Lesion location and extent was verified by NeuN immunolabeling and Nissl stain (Figure 1). Confirmed BSTpm lesions were centered approximately 0.8 mm posterior to bregma according to the Paxinos and Watson atlas. The overall size of the lesions was relatively consistent but was not large enough to destroy the entire principal nucleus, usually sparing the ventral tip, while moderate damage was observed laterally in the

Discussion

Consistent with our previous work, this study indicates that the BSTpm, which includes the principal nucleus of the BST, plays a major role in the inhibition of HPA axis reactivity to an acute stress challenge. The data replicate our previous findings that lesions of the posterior medial BST region enhance stress-induced PVN activation of c-fos mRNA and increase plasma ACTH and corticosterone responses to restraint stress (Choi et al., 2007). In addition, lesions of the posterior medial regions

Role of the funding source

This study was supported by MH49698 (JPH), DA16466 (MMO), DK67820 (YMU), NS07453 (NKE), and DK59803 (ARF). None of these sources had any further role in the study's design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication.

Conflict of interest

All authors have no conflicts of interest within three years of the beginning of this study that could inappropriately influence, or be perceived to influence the work in this study.

Acknowledgments

Special thanks to Kenny Jones, Dr. Nancy Mueller, Ben Packard, Dr. Miyuki Tauchi, and Ingrid Thomas for their technical assistance in this study. We would also like to thank Dr. Matthias Tschoep for the use of his microscopic and surgical equipments.

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