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The anteroventral region of the bed nucleus of the stria terminalis (BST) stimulates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress. However, the role of the anterior BST nuclei in chronic drive of the HPA axis has yet to be established. Therefore, this study tests the role of the anteroventral BST in physiological responses to chronic drive, using a chronic variable stress (CVS) model. Male Sprague-Dawley rats received either bilateral ibotenate lesions, targeting the anteroventral BST, or vehicle injection into the same region. Half of the lesion and control rats were exposed to a 14-d CVS paradigm consisting of twice-daily exposure to unpredictable, alternating stressors. The remaining rats were nonhandled control animals that remained in home cages. On the morning after the end of CVS exposure, all rats were exposed to a novel restraint stress challenge. CVS induced attenuated body weight gain, adrenal hypertrophy, thymic involution, and enhanced CRH mRNA in hypophysiotrophic neurons of the hypothalamic paraventricular nucleus, none of which were affected by anteroventral BST lesions. In the absence of CVS, lesions attenuated the plasma corticosterone and paraventricular nucleus c-fos mRNA responses to the acute restraint stress. In contrast, lesions of the anteroventral BST elevated plasma ACTH and corticosterone responses to novel restraint in the rats previously exposed to CVS. These data suggest that the anterior BST plays very different roles in integrating acute stimulation and chronic drive of the HPA axis, perhaps mediated by chronic stress-induced recruitment of distinct BST cell groups or functional reorganization of stress-integrative circuits.

It is well established that estrogens markedly enhance the glucocorticoid response to acute stress in females. However, the precise mechanism responsible for this regulation is poorly understood. Here, we tested whether estrogens enhance the activation of the paraventricular nucleus (PVN) of the hypothalamus by measuring stress-induced c-fos mRNA expression in the PVN of restraint-stressed ovariectomized (OVX) rats treated with physiologically relevant doses of estradiol (E(2)), the major female estrogen. As expected, E(2) enhanced plasma corticosterone responses to restraint in OVX females. However, E(2) markedly attenuated the stress-induced c-fos gene expression in the PVN and inhibited plasma ACTH responses in these animals. Furthermore, E(2)-inhibitory effects were mimicked by progesterone (P) alone or in combination with E(2). Interestingly, the suppressive central effects of both E(2) and P were apparently independent of basal paraventricular corticotropin-releasing hormone (CRH) transcription, since these ovarian steroids did not significantly affect PVN CRH mRNA expression in unstressed rats. These unexpected findings suggested that E(2) promotes glucocorticoid hypersecretion in females by additional peripheral (i.e., adrenal) mechanisms. Indeed, E(2) markedly enhanced plasma corticosterone responses and adrenal corticosterone content in dexamethasone-blocked OVX rats challenged with varying doses of exogenous ACTH. These results suggest that enhanced adrenal sensitive to ACTH is an important physiological mechanism mediating E(2)-related glucocorticoid hypersecretion in stressed females.

Development of the hypothalamo-pituitary-adrenocortical (HPA) axis is marked by a diminution in stress responsiveness early in the postnatal period (days 4-14 in the rat). This 'stress hyporesponsive period' (SHRP) is thought to be at least in part centrally mediated. To investigate central mechanisms underlying the SHRP, this study assessed expression of glutamic acid decarboxylase (GAD) 67 in key stress-regulatory regions in the forebrain following acute stress with or without prior maternal deprivation. This isoform of GAD is known to be induced by stress in the adult and is believed to be a major contributor to production of the inhibitory neurotransmitter GABA under stimulated conditions. Expression of GAD67 mRNA was increased in the hippocampus, central amygdala and dorsomedial hypothalamus in pups tested early in the SHRP (day 6) or after its conclusion (day 18). In contrast, restraint caused a down-regulation of GAD67 mRNA in these structures when tested later in the SHRP (day 12). GAD67 mRNA expression was not affected by prior maternal deprivation in these regions. Reduced GABA production in the hippocampus (interneurons) is consistent with enhanced HPA axis inhibition, whereas reduced amygdalar expression predicts impaired stress excitation. Expression of GAD67 mRNA in the bed nucleus of the stria terminalis (BST) was minimally affected by acute restraint or maternal deprivation during the SHRP. However, older animals showed down-regulation of basal expression following maternal deprivation and substantial GAD67 mRNA up-regulation in both deprived and non-deprived groups following acute restraint. In contrast, non-responsiveness of the BST during the SHRP suggests either that BST GABA circuits are not actively engaged by stressors during this period or that circuits regulating BST GAD67 production are not yet in place. Overall, the data implicate forebrain GABA circuits in inhibition of HPA axis activity during the SHRP.

Limbic and cortical neurocircuits profoundly influence hypothalamic-pituitary-adrenal (HPA) axis responses to stress yet have little or no direct projections to the hypothalamic paraventricular nucleus (PVN). Numerous lines of evidence suggest that the bed nucleus of the stria terminalis (BST) is well positioned to relay limbic information to the PVN. The BST comprises multiple anatomically distinct nuclei, of which some are known to receive direct limbic and/or cortical input and to heavily innervate the PVN. Our studies test the hypothesis that subregions of the BST differentially regulate HPA axis responses to acute stress. Male Sprague Dawley rats received bilateral ibotenate lesions, targeting either the principal nucleus in the posterior BST or the dorsomedial/fusiform nuclei in the anteroventral BST. Posterior BST lesions elevated plasma ACTH and corticosterone in response to acute restraint stress, increased stress-induced PVN c-fos mRNA, and elevated PVN corticotropin-releasing hormone (CRH) and parvocellular arginine vasopressin (AVP) mRNA expression relative to sham-lesion animals. In contrast, anterior BST lesions attenuated the plasma corticosterone response and decreased c-fos mRNA induction in the PVN but did not affect CRH and parvocellular AVP mRNA expression in the PVN. These data suggest that posterior BST nuclei are involved in inhibition of the HPA axis, whereas the anteroventral BST nuclei are involved in HPA axis excitation. The results indicate that the BST contains functional subdomains that play different roles in integrating and processing limbic information in response to stress and further suggest that excitatory as well as inhibitory limbic information is funneled through these important cell groups.

The adrenal gland is an essential stress-responsive organ that is part of both the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullary system. Chronic stress exposure commonly increases adrenal weight, but it is not known to what extent this growth is due to cellular hyperplasia or hypertrophy and whether it is subregion specific. Moreover, it is not clear whether increased production of adrenal glucocorticoid after chronic stress is due to increased sensitivity to adrenocorticotropic hormone (ACTH) vs. increased maximal output. The present studies use a 14-day chronic variable stress (CVS) paradigm in adult male rats to assess the effects of chronic stress on adrenal growth and corticosterone steroidogenesis. Exogenous ACTH administration (0-895 ng/100 g body wt) to dexamethasone-blocked rats demonstrated that CVS increased maximal plasma and adrenal corticosterone responses to ACTH without affecting sensitivity. This enhanced function was associated with increased adrenal weight, DNA and RNA content, and RNA/DNA ratio after CVS, suggesting that both cellular hyperplasia and hypertrophy occurred. Unbiased stereological counting of cells labeled for Ki67 (cell division marker) or 4,6-diamidino-2-phenylindole (nuclear marker), combined with zone specific markers, showed that CVS induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Collectively, these results demonstrate that increased adrenal weight after CVS is due to hyperplasia and hypertrophy that occur in specific adrenal subregions and is associated with increased maximal corticosterone responses to ACTH. These chronic stress-induced changes in adrenal growth and function may have implications for patients with stress-related disorders.

Appropriate regulatory control of the hypothalamo-pituitary-adrenocortical stress axis is essential to health and survival. The following review documents the principle extrinsic and intrinsic mechanisms responsible for regulating stress-responsive CRH neurons of the hypothalamic paraventricular nucleus, which summate excitatory and inhibitory inputs into a net secretory signal at the pituitary gland. Regions that directly innervate these neurons are primed to relay sensory information, including visceral afferents, nociceptors and circumventricular organs, thereby promoting 'reactive' corticosteroid responses to emergent homeostatic challenges. Indirect inputs from the limbic-associated structures are capable of activating these same cells in the absence of frank physiological challenges; such 'anticipatory' signals regulate glucocorticoid release under conditions in which physical challenges may be predicted, either by innate programs or conditioned stimuli. Importantly, 'anticipatory' circuits are integrated with neural pathways subserving 'reactive' responses at multiple levels. The resultant hierarchical organization of stress-responsive neurocircuitries is capable of comparing information from multiple limbic sources with internally generated and peripherally sensed information, thereby tuning the relative activity of the adrenal cortex. Imbalances among these limbic pathways and homeostatic sensors are likely to underlie hypothalamo-pituitary-adrenocortical dysfunction associated with numerous disease processes.