Trends in Neurosciences
Volume 20, Issue 2, 1 February 1997, Pages 78-84
Journal home page for Trends in Neurosciences

Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis

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Abstract

Integration of the hypothalamo–pituitary–adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat (`systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures (`processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.

Section snippets

Central co-ordination of glucocorticoid release: role of the paraventricular nucleus

Central control of glucocorticoid secretion is regulated principally by a select population of neurosecretory neurons in the hypothalamic paraventricular nucleus (PVN). Upon stimulation by stress, these neurons secrete a cocktail of adrenocorticotrophic hormone (ACTH) secretagogues, the most important of which are corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), into the pituitary portal circulation[5]. Subsequent increases in circulating ACTH then drive synthesis and

Initiating the stress response

Excitation of the HPA axis is driven by select central stress circuits (Table 1). Notable among these are brainstem catecholamine-producing pathways, which project directly to CRH-containing neurons of the PVN (Refs 12, 13). Catecholaminergic drive appears to promote HPA secretory activity following hemorrhage, hypotension and respiratory distress[14], and might play a role in ACTH responses to immune challenge as well[15]. The excitatory effects of catecholamines on HPA activation appear to be

Limiting the stress response

The importance of maintaining glucocorticoid secretion within tolerable limits requires efficient mechanisms for inhibiting stress-integrative PVN neurons. This process appears to be accomplished by multiple pathways (Table 2). Notably, glucocorticoid injections into the PVN region downregulate CRH mRNA, decrease ACTH secretion and inhibit medial parvocellular PVN neurons[5], suggesting that glucocorticoid negative feedback acts at the PVN neuron itself. The capacity for direct glucocorticoid

Hypothesis: `processive' vs `systemic' stress pathways

The literature suggests that the stress-regulatory circuit activated by a particular stressor is crucially dependent on stimulus attributes (see Table 1, Table 2). In general, limbic stress pathways are most sensitive to stressors involving higher-order sensory processing. For example, HPA responses to restraint, fear conditioning or exposure to a novel environment are affected by lesions of the prefrontal cortex, hippocampus or amygdala. These stressors have common features: (1) all require

Brain stress regulation in disease

Neuronally mediated control of the hypothalamic PVN (and subsequent glucocorticoid secretion) is clearly crucial for maintenance of health and well-being under basal and `stressful' conditions. The data reviewed above add important insight to the understanding of human stress-related HPA pathology. For example, alterations in neuroendocrine control induced by life stresses are likely to be associated with limbic dysfunction, involving regions such as the hippocampal formation, medial prefrontal

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