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Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response

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ABSTRACT

The hypothalamo‐pituitary‐adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans‐synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress‐induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological). © 2016 American Physiological Society. Compr Physiol 6:603‐621, 2016.

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Figure 1. Figure 1. Organization of the HPA axis. HPA axis stress responses are initiated by CRH neurons in the PVN. Stressors cause release of CRH into the hypophysial portal vessels, which transport peptide to the anterior pituitary to enable access to corticotrophs. Stimulated corticotrophs then release ACTH into the systemic circulation, whereby it promotes synthesis and secretion of glucocorticoids [cortisol in some species (e.g., man), corticosterone in others (e.g., rats and mice)] at the adrenal cortex. Glucocorticoids are then secreted into the systemic circulation and can access cognate receptors in virtually every organ system, including the brain. Reproduced from (), with permission.
Figure 2. Figure 2. Temporal dynamics of HPA axis stress responses. In response to stress, ACTH is released within minutes of stimulation. The extent of ACTH release is limited by rapid, nongenomic fast feedback mechanisms (usually peaking within 15 min of stressor onset) (see text). Due to the time needed for ACTH to access the adrenal cortex and promote glucocorticoid synthesis and release, there is a substantial delay between time‐to‐peak for corticosterone relative to ACTH (usually within 30‐60 min). In addition to shutdown by fast feedback inhibition of ACTH release, the time course of the corticosterone response (usually on the order of 2 h) can be modulated by delayed glucocorticoid feedback as well as factors controlling glucocorticoid metabolism. The timing of both ACTH and corticosterone responses are dependent on stressor modality and intensity. Modified from (), with permission.
Figure 3. Figure 3. Neural mechanisms of acute stress excitation. Data suggest corticotropin releasing hormone neurons in the medial dorsal paraventricular nucleus (mpPVN) can be driven by neurons communicating homeostatic challenge, including the NTS, among others. The PVN also has numerous connections with hypothalamic nuclei and subcortical telencephalic structures, including excitatory [posterior hypothalamus (PH), ventrolateral region of the BST] and inhibitory [medial preoptic nucleus (mPOA), dorsomedial nucleus (DMH), periPVN, and posterior BST] inputs. Inhibitory input to the PVN provides a substantial inhibitory tone, which can be disrupted by inhibition from upstream sites such as the medial and central amygdaloid nuclei (MeA, CeA), providing a mechanism for transsynaptic disinhibition from the limbic forebrain. There is also some evidence suggesting that some cortical regions, such as the infralimbic region (il) of the medial prefrontal cortex, may also provide transsynaptic excitation, perhaps via relays in the brainstem. There is less evidence for excitatory input from other forebrain stress circuits, such as the ventral subiculum (vSUB), prelimbic division of the mPFC or paraventricular thalamus. Input from limbic regions may also access the PVN by interaction with local interneurons in the PVN surround (periPVN). Open circles: inhibitory (e.g., GABAergic) neurons; closed circles: excitatory (e.g., glutamatergic) neurons; squares: inhibitory input; arrowheads: excitatory inputs. Adapted from (), with permission.
Figure 4. Figure 4. Neural mechanisms of acute stress inhibition. As noted, the PVN receives substantial inhibitory input from hypothalamic (mPOA, DMH, and periPVN) and medial forebrain (BST) structures. The regions receive excitatory inputs from forebrain structures such as the IL, PL, and vSUB, which are thought to mediate trans‐synaptic inhibition of HPA axis stress responses. Upstream limbic pathways may also limit drive of the mpPVN by way of local inhibition of HPA axis excitatory circuits, for example, the NTS and/or PH. See Figure legend for abbreviations. Adapted from (), with permission.
Figure 5. Figure 5. Habituation of glucocorticoid stress responses following chronic stress, often observed after repeated or predictable stressor exposure. Modified from (), with permission.
Figure 6. Figure 6. Potential glucocorticoid profiles seen following nonhabituating chronic stressors (e.g., seen after chronic unpredictable stress, chronic social stress, or severe stress regimens). Depending on both the regimen and the individual, chronic stress profiles may be manifest as increased basal glucocorticoid secretion (usually at the time of the circadian nadir); delayed shut‐off of the stress response (due to reduced feedback efficacy); facilitated or sensitized responses to novel stressors; or in extreme cases, hyporesponsiveness driven by adrenal exhaustion. Modified from (), with permission.
Figure 7. Figure 7. Neural mechanisms controlling chronic stress regulation of the HPA axis. Pathways responsible for drive of the HPA axis under chronic stress are not as well understood as those mediating acute response. There is strong evidence that the PVT, which is not involved in acute stress excitation or inhibition, is required for both stress habituation and stress facilitation, suggesting a role in communicating stress chronicity. Importantly, the PVT has extensive reciprocal projections to the IL, PL, and vSUB, as well as projections to the area of the BST. Neuronal activation studies indicate the existence of a small network of structures that are differentially activated by chronic unpredictable stress (relative to restraint), including the IL, PL, PH, and NTS. Importantly, the PH and NTS are both connected with the IL, and both mediate acute stress excitation, suggesting a possible integrated circuit mediating chronic stress drive. Finally, chronic stress increases tone of CRH‐expressing stress circuitry, suggesting that CRH systems may be recruited by chronic stress and participate in HPA axis hyperdrive. See Figure 3 legend for abbreviations. Adapted from (), with permission.
Figure 8. Figure 8. Inverted U‐shaped relationship between increasing levels of glucocorticoids (arrow) and ‘systems performance’ (e.g., spatial memory). Optimal systems performance is generally observed at intermediate levels of glucocorticoid availability, consistent with the need for glucocorticoids to supply an appropriate context for adaptation. Performance is generally degraded if glucocorticoid secretion is insufficient or hyperresponsive. See deKloet (1998) () for discussion. Modified from (), with permission.


Figure 1. Organization of the HPA axis. HPA axis stress responses are initiated by CRH neurons in the PVN. Stressors cause release of CRH into the hypophysial portal vessels, which transport peptide to the anterior pituitary to enable access to corticotrophs. Stimulated corticotrophs then release ACTH into the systemic circulation, whereby it promotes synthesis and secretion of glucocorticoids [cortisol in some species (e.g., man), corticosterone in others (e.g., rats and mice)] at the adrenal cortex. Glucocorticoids are then secreted into the systemic circulation and can access cognate receptors in virtually every organ system, including the brain. Reproduced from (), with permission.


Figure 2. Temporal dynamics of HPA axis stress responses. In response to stress, ACTH is released within minutes of stimulation. The extent of ACTH release is limited by rapid, nongenomic fast feedback mechanisms (usually peaking within 15 min of stressor onset) (see text). Due to the time needed for ACTH to access the adrenal cortex and promote glucocorticoid synthesis and release, there is a substantial delay between time‐to‐peak for corticosterone relative to ACTH (usually within 30‐60 min). In addition to shutdown by fast feedback inhibition of ACTH release, the time course of the corticosterone response (usually on the order of 2 h) can be modulated by delayed glucocorticoid feedback as well as factors controlling glucocorticoid metabolism. The timing of both ACTH and corticosterone responses are dependent on stressor modality and intensity. Modified from (), with permission.


Figure 3. Neural mechanisms of acute stress excitation. Data suggest corticotropin releasing hormone neurons in the medial dorsal paraventricular nucleus (mpPVN) can be driven by neurons communicating homeostatic challenge, including the NTS, among others. The PVN also has numerous connections with hypothalamic nuclei and subcortical telencephalic structures, including excitatory [posterior hypothalamus (PH), ventrolateral region of the BST] and inhibitory [medial preoptic nucleus (mPOA), dorsomedial nucleus (DMH), periPVN, and posterior BST] inputs. Inhibitory input to the PVN provides a substantial inhibitory tone, which can be disrupted by inhibition from upstream sites such as the medial and central amygdaloid nuclei (MeA, CeA), providing a mechanism for transsynaptic disinhibition from the limbic forebrain. There is also some evidence suggesting that some cortical regions, such as the infralimbic region (il) of the medial prefrontal cortex, may also provide transsynaptic excitation, perhaps via relays in the brainstem. There is less evidence for excitatory input from other forebrain stress circuits, such as the ventral subiculum (vSUB), prelimbic division of the mPFC or paraventricular thalamus. Input from limbic regions may also access the PVN by interaction with local interneurons in the PVN surround (periPVN). Open circles: inhibitory (e.g., GABAergic) neurons; closed circles: excitatory (e.g., glutamatergic) neurons; squares: inhibitory input; arrowheads: excitatory inputs. Adapted from (), with permission.


Figure 4. Neural mechanisms of acute stress inhibition. As noted, the PVN receives substantial inhibitory input from hypothalamic (mPOA, DMH, and periPVN) and medial forebrain (BST) structures. The regions receive excitatory inputs from forebrain structures such as the IL, PL, and vSUB, which are thought to mediate trans‐synaptic inhibition of HPA axis stress responses. Upstream limbic pathways may also limit drive of the mpPVN by way of local inhibition of HPA axis excitatory circuits, for example, the NTS and/or PH. See Figure legend for abbreviations. Adapted from (), with permission.


Figure 5. Habituation of glucocorticoid stress responses following chronic stress, often observed after repeated or predictable stressor exposure. Modified from (), with permission.


Figure 6. Potential glucocorticoid profiles seen following nonhabituating chronic stressors (e.g., seen after chronic unpredictable stress, chronic social stress, or severe stress regimens). Depending on both the regimen and the individual, chronic stress profiles may be manifest as increased basal glucocorticoid secretion (usually at the time of the circadian nadir); delayed shut‐off of the stress response (due to reduced feedback efficacy); facilitated or sensitized responses to novel stressors; or in extreme cases, hyporesponsiveness driven by adrenal exhaustion. Modified from (), with permission.


Figure 7. Neural mechanisms controlling chronic stress regulation of the HPA axis. Pathways responsible for drive of the HPA axis under chronic stress are not as well understood as those mediating acute response. There is strong evidence that the PVT, which is not involved in acute stress excitation or inhibition, is required for both stress habituation and stress facilitation, suggesting a role in communicating stress chronicity. Importantly, the PVT has extensive reciprocal projections to the IL, PL, and vSUB, as well as projections to the area of the BST. Neuronal activation studies indicate the existence of a small network of structures that are differentially activated by chronic unpredictable stress (relative to restraint), including the IL, PL, PH, and NTS. Importantly, the PH and NTS are both connected with the IL, and both mediate acute stress excitation, suggesting a possible integrated circuit mediating chronic stress drive. Finally, chronic stress increases tone of CRH‐expressing stress circuitry, suggesting that CRH systems may be recruited by chronic stress and participate in HPA axis hyperdrive. See Figure 3 legend for abbreviations. Adapted from (), with permission.


Figure 8. Inverted U‐shaped relationship between increasing levels of glucocorticoids (arrow) and ‘systems performance’ (e.g., spatial memory). Optimal systems performance is generally observed at intermediate levels of glucocorticoid availability, consistent with the need for glucocorticoids to supply an appropriate context for adaptation. Performance is generally degraded if glucocorticoid secretion is insufficient or hyperresponsive. See deKloet (1998) () for discussion. Modified from (), with permission.
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Further Reading

Bornstein SR, Engeland WC, Ehrhart-Bornstein M and Herman JP.  Dissociation of ACTH and glucocorticoids.  Trends Endocrinol Metab 19: 175-180, 2008.  Highlights work demonstrating regulation of corticosteroid secretion at the level of the adrenal.

Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H, Bell ME, Bhatnagar S, Laugero KD and Manalo S.  Chronic stress and obesity: a new view of "comfort food".  Proc Natl Acad Sci U S A 100: 11696-11701, 2003.  An influential paper positing both the importance of CRH neuron recruitment to chronic stress drive and their regulation by peripheral metabolic signals.

De Kloet ER, Vreugdenhil E, Oitzl MS and Joels M.  Brain corticosteroid receptor balance in health and disease.  Endocr Rev 19: 269-301, 1998.  Definitive exposition of the interplay between MR and GR, wedding the 'inverted U-shaped curve' to glucocorticoid signaling mechanisms.

Keller-Wood M and Dallman MF.  Corticosteroid inhibition of ACTH secretion.  Endocrine Rev. 5: 1-24, 1984.  A still-definitive synopsis of a vast literature on the problem of negative feedback regulation of the HPA axis.

Nederhof E and Schmidt MV.  Mismatch or cumulative stress: toward an integrated hypothesis of programming effects.  Physiol Behav 106: 691-700, 2012.  Elegant discussion of the match:mismatch hypothesis of how early life stress affects stress reactivity later in life.


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How to Cite

James P. Herman, Jessica M. McKlveen, Sriparna Ghosal, Brittany Kopp, Aynara Wulsin, Ryan Makinson, Jessie Scheimann, Brent Myers. Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response. Compr Physiol 2016, 6: 603-621. doi: 10.1002/cphy.c150015