Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness

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Abstract

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.

Introduction

The hypothalamo–pituitary–adrenocortical (HPA) axis plays a vital role in adaptation of the organism to homeostatic challenge. Activation of the HPA system culminates in secretion of glucocorticoids, which act at multiple levels to redirect bodily energy resources [198], [210], [262]. These hormones are recognized by glucocorticoid receptor molecules in numerous organ systems, and act by genomic mechanisms to modify transcription of key regulatory proteins [198], [210]. Emerging evidence suggests that glucocorticoids also act by non-genomic mechanisms on cell signaling processes [208], [217], and in such fashion have rapid actions on homeostatic regulation.

The end effects of glucocorticoid action include energy mobilization (glycogenolysis) in the liver, suppression of innate immunity in immune organs, inhibition of bone and muscle growth, potentiation of sympathetic nervous system-mediated vasoconstriction, proteolysis and lipolysis, suppression of reproductive function along the hypothalamo–pituitary–gonadal axis, and behavioral depression (see [198], [210]). The spectrum of effects have led to the hypothesis that glucocorticoids act to restore homeostasis following disruption [210]; for example, increasing glucose can replenish lost energy stores; inhibiting T-cell proliferation will control the inflammatory response; and inhibiting other hormonal systems reduces expenditure of energy on processes unrelated to the immediate challenge. These ‘restorative’ processes are generally catabolic in nature, and naturally if extended in time can take a powerful toll on the organism. Indeed, glucocorticoid hypersecretion is implicated as a major deleterious factor in the aging process [171], [172], [261], and is known to accompany numerous long-term metabolic, affective, and psychotic disease states (see [111], [198], for review).

Accordingly, adequate control of glucocorticoids needs to be accomplished by the organism. Such ‘negative feedback’ control is efficiently exerted in healthy organisms, and involves both rapid and genomic actions at the pituitary and at multiple sites in the brain (discussed below). Thus, a HPA response is generally characterized by a temporally regulated ‘surge’ of ACTH release followed by a ‘shut-off’ signal generated by glucocorticoid as well as neuronal feedback (see Fig. 1, [151]). The ACTH ‘surge’ is initiated by a discrete population of hypophysiotrophic neurons in the medial parvocellular division of the paraventricular hypothalamic nucleus (PVN) [6], [319]. This small population of cells (approximately 4000 in rat [290]) produce a number of ACTH-releasing factors. Of these, corticotropin releasing hormone (CRH) is required for normal ACTH release under both basal and stressed conditions [6], [319] and is the defining phenotypic feature of this cell type. The most important co-expressed peptide is arginine vasopressin, which synergizes with CRH to enhance the ‘gain’ of the ACTH response [6], [187], [319]. These neurons also produce numerous other peptides and neurotransmitters [155], and may thus have their net activity orchestrated by multiple neuroactive species. Once released by the corticotropes, ACTH travels through the systemic circulation and promotes on-site synthesis and secretion of corticosteroids at the adrenal cortex. While ACTH is the major modulator of corticosteroid release, adrenocortical output can be modulated by neuronal inputs that adjust responsivity to ACTH [304].

The HPA axis operates in two equally important domains of activity. Under relatively unstressed conditions, glucocorticoid secretion undergoes a daily rhythm, with peak secretion occurring at the initiation of the waking cycle in most vertebrate organisms [151]. Secretion during the waking phase permits circulating glucocorticoids to partially occupy glucocorticoid receptors [238], and is believed to be critical for optimizing functional tone of numerous systems [67]. For example, partial occupation of hippocampal glucocorticoid receptors is required for efficient performance of learning and memory tasks in rats [67], [72], suggesting that glucocorticoids may ‘set the tone’ for information processing in the brain. Control of this rhythmic activity is coordinated by inputs from the suprachiasmatic nucleus [67], [72], the critical pacemaker of numerous bodily rhythms.

The second domain of HPA action, and the principal topic of this review, is control of corticosteroid secretion following stress. Upon receipt of a ‘stressful’ stimulus, defined here as a real or predicted threat to homeostasis, the brain initiates an ACTH surge to promote adrenocortical activation. The notion of ‘real’ or ‘predicted’ is important, as it highlights what we hypothesize are two distinct realms of stress activation. A ‘real’ stressor represents a genuine homeostatic challenge that is recognized by somatic, visceral or circumventricular sensory pathways. These stressors would include such things as marked changes in cardiovascular tone, respiratory distress, visceral or somatic pain, and blood-borne cytokine or chemokine factors signaling infection or inflammation (see Table 1). As these represent a response of the body to a very real sensory stimulus, we consider these responses to be ‘reactive.’ However, HPA activation can also occur in the absence of primary sensory stimuli signaling homeostatic disruption. These responses are centrally generated in the absence of a physiological challenge, and represent an effort of the organism to mount a glucocorticoid response in anticipation of, rather than as a reaction to, homeostatic disruption. These ‘anticipatory’ responses are either generated by conditioning (‘memory’) or by innate, species-specific predispositions (e.g., recognition of predators, recognition of danger associated with heights or open spaces) (Table 1). The ‘reactive-anticipatory’ distinction is experience dependent; the environment associated with a reactive stressor can be itself conditioned, resulting in an ‘anticipatory’ response when the conditioned stimuli are next encountered.

The mnemonic aspects of anticipatory stressors are important determinants of the HPA response. As noted above, the HPA response is energetically costly and cannot be over-engaged without deleterious consequences [197]. As such, the brain can generate memory-dependent inhibitory and excitatory traces to control glucocorticoid responses. For example, mnemonic circuits can diminish responsiveness to contextual stimuli with repeated exposure (habituation), or activate responses to innocuous cues that are associated with an emergent threat. The wide spectrum of these responses is under exquisite control by limbic brain regions such as the hippocampus, amygdala, and prefrontal cortex.

The remainder of this review will be devoted to delineating critical circuits responsible for regulation of the HPA stress response, and developing a framework for understanding the possible role of these hierarchical circuits in stress-related disease states.

Section snippets

Direct PVN connections

The medial parvocellular PVN is in receipt of synaptic innervation from a relatively circumspect set of central nervous system structures, summarized in Fig. 2. In general, PVN projecting neurons are localized in regions known to receive first- or second-order inputs from somatic nociceptors, visceral afferents or humoral sensory pathways. As such, the majority of PVN-projecting neurons are positioned to evoke rapid, reflexive activation of the HPA axis.

Intrinsic PVN information processing

The PVN is well positioned to receive direct input from blood- and CSF-borne factors (Fig. 6). This nucleus is endowed with a dense capillary plexus [200], [307]; while there is no evidence that these vessels are fenestrated, it is clear that this plexus can allow ready access of blood–brain barrier permeable factors, including steroid hormones. Indeed, there is ample evidence that glucocorticoids exert local feedback effects in the region of the PVN, inhibiting CRH gene expression and

Indirect paths to the PVN

Previous work reveals rich interactions between limbic brain structures and HPA activation. These structures, including regions such as the hippocampus, prefrontal cortex, amygdala, septum, and midline thalamus, are critical for emotional responses and memory, and are thus logical candidates for modulating pituitary–adrenal secretions with respect to previous experience. As such, these structures likely play a major role in anticipatory stress responses. Importantly, all of the above regions

Methodological considerations in stress research: sources of disagreements?

Before generalities can be drawn concerning the voluminous literature on neurocircuit regulation, sources for some of the disagreements among studies need to be considered. Disagreements are most pronounced among limbic-HPA studies, where conflicting data exist regarding the effects of hippocampal and central amygdalar lesions on ACTH secretion (see above). While some of the conflict can be resolved by consideration of stress modality, there are some instances where very similar experiments

Acknowledgments

This work was supported by NIH Grants MH49698 to J.P.H., MH56577 to W.E.C., MH60819 to J.P.H. and W.E.C., and NIH NRSA Grant MH65770 to N.K.M. We thank Dr. Dana Ziegler, Dr. Chantal Prewitt, Mark Dolgas, Garrett Bowers, and Melanie Emmert for their efforts on various components of these projects. We also acknowledge the late Bryan Bodie; his scientific and personal contributions are sorely missed.

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