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Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response

James P. Herman, Jessica M. McKlveen, Sriparna Ghosal, Brittany Kopp, Aynara Wulsin, Ryan Makinson, Jessie Scheimann, Brent Myers

10.1002/cphy.c150015

Source: null

Published online: March 2016

Full Article on Wiley Online Library



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 (117), 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 (69), 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 (79), 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 3 legend for abbreviations. Adapted from (79), with permission.
Figure 5. Figure 5. Habituation of glucocorticoid stress responses following chronic stress, often observed after repeated or predictable stressor exposure. Modified from (69), 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 (69), 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 (79), 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) (32) for discussion. Modified from (69), 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 (117), 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 (69), 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 (79), 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 3 legend for abbreviations. Adapted from (79), with permission.


Figure 5. Habituation of glucocorticoid stress responses following chronic stress, often observed after repeated or predictable stressor exposure. Modified from (69), 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 (69), 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 (79), 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) (32) for discussion. Modified from (69), with permission.
References
 1. Accorsi‐Mendonca D , Machado BH . Synaptic transmission of baro‐ and chemoreceptors afferents in the NTS second order neurons. Auton Neurosci 175: 3‐8, 2013.
 2. Aguilera G . Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol 15: 321‐350, 1994.
 3. Aguilera G , Rabadan‐Diehl C . Vasopressinergic regulation of the hypothalamic‐pituitary‐adrenal axis: implications for stress adaptation. Regul Pept 96: 23‐29, 2000.
 4. Akana SF , Dallman MF , Bradbury MJ , Scribner KA , Strack AM , Walker CD . Feedback and facilitation in the adrenocortical system: Unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress. Endocrinology 131: 57‐68, 1992.
 5. Albeck DS , McKittrick CR , Blanchard DC , Blanchard RJ , Nikulina J , McEwen BS , Sakai RR . Chronic social stress alters levels of corticotropin‐releasing factor and arginine vasopressin mRNA in rat brain. J Neurosci 17: 4895‐4903, 1997.
 6. Albert K , Pruessner J , Newhouse P . Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. Psychoneuroendocrinology 59: 14‐24, 2015.
 7. Antoni FA . Hypothalamic control of adrenocorticotropin secretion: Advances since the discovery of 41‐residue corticotropin‐releasing factor. Endocrine Rev 7: 351‐378, 1986.
 8. Armario A , Castellanos JM . Effect of acute and chronic stress on testosterone secretion in male rats. J Endocrinol Invest 7: 659‐661, 1984.
 9. Baskin DG , Figlewicz Lattemann D , Seeley RJ , Woods SC , Porte D, Jr. , Schwartz MW . Insulin and leptin: Dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res 848: 114‐123, 1999.
 10. Bean AJ , Roth RH . Extracellular dopamine and neurotensin in rat prefrontal cortex in vivo: Effects of median forebrain bundle stimulation frequency, stimulation pattern, and dopamine autoreceptors. J Neurosci 11: 2694‐2702, 1991.
 11. Belanger A , Candas B , Dupont A , Cusan L , Diamond P , Gomez JL , Labrie F . Changes in serum concentrations of conjugated and unconjugated steroids in 40‐ to 80‐year‐old men. J Clin Endocrinol Metab 79: 1086‐1090, 1994.
 12. Benjannet S , Rondeau N , Day R , Chretien M , Seidah NG . PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc Natl Acad Sci U S A 88: 3564‐3568, 1991.
 13. Bethin KE , Vogt SK , Muglia LJ . Interleukin‐6 is an essential, corticotropin‐releasing hormone‐independent stimulator of the adrenal axis during immune system activation. Proc Natl Acad Sci U S A 97: 9317‐9322, 2000.
 14. Bhatnagar S , Dallman M . Neuroanatomical basis for facilitation of hypothalamic‐pituitary‐adrenal responses to a novel stressor after chronic stress. Neuroscience 84: 1025‐1039, 1998.
 15. Bhatnagar S , Huber R , Nowak N , Trotter P . Lesions of the posterior paraventricular thalamus block habituation of hypothalamic‐pituitary‐adrenal responses to repeated restraint. J Neuroendocrinol 14: 403‐410, 2002.
 16. Blanchard DC , Sakai RR , McEwen B , Weiss SM , Blanchard RJ . Subordination stress: Behavioral, brain, and neuroendocrine correlates. Behav Brain Res 58: 113‐121, 1993.
 17. Bornstein SR , Engeland WC , Ehrhart‐Bornstein M , Herman JP . Dissociation of ACTH and glucocorticoids. Trends Endocrinol Metab 19: 175‐180, 2008.
 18. Boscaro M , Paoletta A , Scarpa E , Barzon L , Fusaro P , Fallo F , Sonino N . Age‐related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man. J Clin Endocrinol Metab 83: 1380‐1383, 1998.
 19. Boyle MP , Kolber BJ , Vogt SK , Wozniak DF , Muglia LJ . Forebrain glucocorticoid receptors modulate anxiety‐associated locomotor activation and adrenal responsiveness. J Neurosci 26: 1971‐1978, 2006.
 20. Carey MP , Deterd CH , de Koning J , Helmerhorst F , de Kloet ER . The influence of ovarian steroids on hypothalamic‐pituitary‐adrenal regulation in the female rat. J Endocrinol 144: 311‐321, 1995.
 21. Choi DC , Evanson NK , Furay AR , Ulrich‐Lai YM , Ostrander MM , Herman JP . The anteroventral bed nucleus of the stria terminalis differentially regulates hypothalamic‐pituitary‐adrenocortical axis responses to acute and chronic stress. Endocrinology 149: 818‐826, 2008.
 22. Choi DC , Furay AR , Evanson NK , Ostrander MM , Ulrich‐Lai YM , Herman JP . Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic‐pituitary‐adrenal axis activity: Implications for the integration of limbic inputs. J Neurosci 27: 2025‐2034, 2007.
 23. Cizza G , Calogero AE , Brady LS , Bagdy G , Bergamini E , Blackman MR , Chrousos GP , Gold PW . Male Fischer 344/N rats show a progressive central impairment of the hypothalamic‐pituitary‐adrenal axis with advancing age. Endocrinology 134: 1611‐1620, 1994.
 24. Clark BJ , Wells J , King SR , Stocco DM . The purification, cloning, and expression of a novel luteinizing hormone‐induced mitochondrial protein in MA‐10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269: 28314‐28322, 1994.
 25. Cole MA , Kalman BA , Pace TW , Topczewski F , Lowrey MJ , Spencer RL . Selective blockade of the mineralocorticoid receptor impairs hypothalamic‐pituitary‐adrenal axis expression of habituation. J Neuroendocrinol 12: 1034‐1042, 2000.
 26. Cullinan WE , Herman JP , Watson SJ . Ventral subicular interaction with the hypothalamic paraventricular nucleus: Evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol 332: 1‐20, 1993.
 27. Cunningham ET, Jr. , Bohn MC , Sawchenko PE . Organization of adrenergic inputs to the paraventricular and supraoptic nuclei of the hypothalamus in the rat. J Comp Neurol 292: 651‐667, 1990.
 28. Cunningham ET, Jr , Sawchenko PE . Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus. J Comp Neurol 274: 60‐76, 1988.
 29. Dallman MF , La Fleur SE , Pecoraro NC , Gomez F , Houshyar H , Akana SF . Minireview: Glucocorticoids ‐ Food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology 145: 2633‐2638, 2004.
 30. Dallman MF , Pecoraro N , Akana SF , La Fleur SE , Gomez F , Houshyar H , Bell ME , Bhatnagar S , Laugero KD , Manalo S . Chronic stress and obesity: A new view of “comfort food”. Proc Natl Acad Sci U S A 100: 11696‐11701, 2003.
 31. Dayas CV , Buller KM , Crane JW , Xu Y , Day TA . Stressor categorization: Acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 14: 1143‐1152, 2001.
 32.De Kloet ER , Vreugdenhil E , Oitzl MS , Joels M . Brain corticosteroid receptor balance in health and disease. Endocr Rev 19: 269‐301, 1998.
 33. DeMaria EJ , Lilly MP , Gann DS . Potentiated hormonal responses in a model of traumatic injury. J Surg Res 43: 45‐51, 1987.
 34. Dent GW , Smith MA , Levine S . The ontogeny of the neuroendocrine response to endotoxin. Brain Res Dev Brain Res 117: 21‐29, 1999.
 35. Der‐Avakian A , Mazei‐Robison MS , Kesby JP , Nestler EJ , Markou A . Enduring deficits in brain reward function after chronic social defeat in rats: Susceptibility, resilience, and antidepressant response. Biol Psychiatry 76: 542‐549, 2014.
 36. Dhabhar FS , McEwen BS , Spencer RL . Adaptation to prolonged or repeated stress—Comparison between rat strains showing intrinsic differences in reactivity to acute stress. Neuroendocrinology 65: 360‐368, 1997.
 37. Di S , Malcher‐Lopes R , Halmos KC , Tasker JG . Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: A fast feedback mechanism. J Neurosci 23: 4850‐4857, 2003.
 38. Di S , Popescu IR , Tasker JG . Glial control of endocannabinoid heterosynaptic modulation in hypothalamic magnocellular neuroendocrine cells. J Neurosci 33: 18331‐18342, 2013.
 39. Dias‐Ferreira E , Sousa JC , Melo I , Morgado P , Mesquita AR , Cerqueira JJ , Costa RM , Sousa N . Chronic stress causes frontostriatal reorganization and affects decision‐making. Science 325: 621‐625, 2009.
 40. Diorio D , Viau V , Meaney MJ . The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamo‐pituitary‐adrenal responses to stress. J Neurosci 13: 3839‐3847, 1993.
 41. Drevets WC . Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126: 413‐431, 2000.
 42. Evanson NK , Tasker JG , Hill MN , Hillard CJ , Herman JP . Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151: 4811‐4819, 2010.
 43. Familari M , Smith AI , Smith R , Funder JW . Arginine vasopressin is a much more potent stimulus to ACTH release from ovine anterior pituitary cells than ovine corticotropin‐releasing factor. 1. In vitro studies. Neuroendocrinology 50: 152‐157, 1989.
 44. Fanselow MS , Dong HW . Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65: 7‐19, 2010.
 45. Feldman D , Mondon CE , Horner JA , Weiser JN . Glucocorticoid and estrogen regulation of corticosteroid‐binding globulin production by rat liver. Am J Physiol 237: E493‐E499, 1979.
 46. Ferguson AV . Angiotensinergic regulation of autonomic and neuroendocrine outputs: Critical roles for the subfornical organ and paraventricular nucleus. Neuroendocrinology 89: 370‐376, 2009.
 47. Figueiredo HF , Bodie BL , Tauchi M , Dolgas CM , Herman JP . Stress integration after acute and chronic predator stress: Differential activation of central stress circuitry and sensitization of the hypothalamo‐pituitary‐adrenocortical axis. Endocrinology 144: 5249‐5258, 2003.
 48. Figueiredo HF , Bruestle A , Bodie B , Dolgas CM , Herman JP . The medial prefrontal cortex differentially regulates stress‐induced c‐fos expression in the forebrain depending on type of stressor. Eur J Neurosci 18: 2357‐2364, 2003.
 49. Figueiredo HF , Dolgas CM , Herman JP . Stress activation of cortex and hippocampus is modulated by sex and stage of estrus. Endocrinology 143: 2534‐2540, 2002.
 50. Figueiredo HF , Ulrich‐Lai YM , Choi DC , Herman JP . Estrogen potentiates adrenocortical responses to stress in female rats. Am J Physiol Endocrinol Metab 292: E1173‐E1182, 2007.
 51. Flak JN , Jankord R , Solomon MB , Krause EG , Herman JP . Opposing effects of chronic stress and weight restriction on cardiovascular, neuroendocrine and metabolic function. Physiol Behav 104: 228‐234, 2011.
 52. Flak JN , Myers B , Solomon MB , McKlveen JM , Krause EG , Herman JP . Role of paraventricular nucleus‐projecting norepinephrine/epinephrine neurons in acute and chronic stress. Eur J Neurosci 39: 1903‐1911, 2014.
 53. Flak JN , Solomon MB , Jankord R , Krause EG , Herman JP . Identification of chronic stress‐activated regions reveals a potential recruited circuit in rat brain. Eur J Neurosci 36: 2547‐2555, 2012.
 54. Furay AR , Bruestle AE , Herman JP . The role of the forebrain glucocorticoid receptor in acute and chronic stress. Endocrinology 149: 5482‐5490, 2008.
 55. Furukawa H , del Rey A , Monge‐Arditi G , Besedovsky HO . Interleukin‐1, but not stress, stimulates glucocorticoid output during early postnatal life in mice. Ann N Y Acad Sci 840: 117‐122, 1998.
 56. Gann DS , Cryer GL , Pirkle JC, Jr . Physiological inhibition and facilitation of adrenocortical response to hemorrhage. Am J Physiol 232: R5‐R9, 1977.
 57. Ghosal S , Bundzikova‐Osacka J , Dolgas CM , Myers B , Herman JP . Glucocorticoid receptors in the nucleus of the solitary tract (NTS) decrease endocrine and behavioral stress responses. Psychoneuroendocrinology 45: 142‐153, 2014.
 58. Ghosal S , Myers B , Herman JP . Role of central glucagon‐like peptide‐1 in stress regulation. Physiol Behav 122: 201‐207, 2013.
 59. Gibbison B , Spiga F , Walker JJ , Russell GM , Stevenson K , Kershaw Y , Zhao Z , Henley D , Angelini GD , Lightman SL . Dynamic pituitary‐adrenal interactions in response to cardiac surgery. Crit Care Med 43: 791‐800, 2015.
 60. Gillies GE , Linton EA , Lowry PJ . Corticotropin‐releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299: 355‐357, 1982.
 61. Gomez F , Lahmame A , de Kloet ER , Armario A . Hypothalamic‐pituitary‐adrenal response to chronic stress in five inbred rat strains: Differential responses are mainly located at the adrenocortical level. Neuroendocrinology 63: 327‐337, 1996.
 62. Gray M , Bingham B , Viau V . A comparison of two repeated restraint stress paradigms on hypothalamic‐pituitary‐adrenal axis habituation, gonadal status and central neuropeptide expression in adult male rats. J Neuroendocrinol 22: 92‐101, 2010.
 63. Gunnar M , Quevedo K . The neurobiology of stress and development. Annu Rev Psychol 58: 145‐173, 2007.
 64. Hadley ME , Haskell‐Luevano C . The proopiomelanocortin system. Ann N Y Acad Sci 885: 1‐21, 1999.
 65. Hanukoglu I . Steroidogenic enzymes: Structure, function, and role in regulation of steroid hormone biosynthesis. J Steroid Biochem Mol Biol 43: 779‐804, 1992.
 66. Hauer D , Kaufmann I , Strewe C , Briegel I , Campolongo P , Schelling G . The role of glucocorticoids, catecholamines and endocannabinoids in the development of traumatic memories and posttraumatic stress symptoms in survivors of critical illness. Neurobiol Learn Mem 112: 68‐74, 2014.
 67. Hauger RL , Thrivikraman KV , Plotsky PM . Age‐related alterations of hypothalamic‐pituitary‐adrenal axis function in male Fischer 344 rats. Endocrinology 134: 1528‐1536, 1994.
 68. Herman JP . Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell Mol Neurobiol 13: 349‐372, 1993.
 69. Herman JP . Neural control of chronic stress adaptation. Front Behav Neurosci 7: 61, 2013.
 70. Herman JP , Adams D , Prewitt C . Regulatory changes in neuroendocrine stress‐integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 61: 180‐190, 1995.
 71. Herman JP , Cullinan WE . Neurocircuitry of stress: Central control of the hypothalamo‐pituitary‐adrenocortical axis. TINS 20: 78‐83, 1997.
 72. Herman JP , Cullinan WE , Ziegler DR , Tasker JG . Role of the paraventricular nucleus microenvironment in stress integration. Eur J Neurosci 16: 381‐385, 2002.
 73. Herman JP , Dolgas CM , Carlson SL . Ventral subiculum regulates hypothalamo‐pituitary‐adrenocortical and behavioural responses to cognitive stressors. Neuroscience 86: 449‐459, 1998.
 74. Herman JP , Figueiredo H , Mueller NK , Ulrich‐Lai Y , Ostrander MM , Choi DC , Cullinan WE . Central mechanisms of stress integration: Hierarchical circuitry controlling hypothalamo‐pituitary‐adrenocortical responsiveness. Front Neuroendocrinol 24: 151‐180, 2003.
 75. Herman JP , Figueiredo HF , Mueller NK , Ostrander MM , Zhang R , Tauchi M , Choi DC , Furay AR , Evanson NK , Nelson EB , Ulrich‐Lai YM . Neurochemical systems regulating the hypothalamo‐pituitary‐adrenocortical axis. In: Blaustein J , Lajtha A , editors. Handbook of Neurochemistry and Molecular Neurobiology Behavioral Neurochemistry, Neuroendocrinology, and Molecular Neurobiology. New York: Springer, 2007, pp. xiv, 954.
 76. Herman JP , Flak J , Jankord R . Chronic stress plasticity in the hypothalamic paraventricular nucleus. Prog Brain Res 170: 353‐364, 2008.
 77. Herman JP , Larson BR , Speert DB , Seasholtz AF . Hypothalamo‐pituitary‐adrenocortical dysregulation in aging F344/Brown‐Norway F1 hybrid rats. Neurobiol Aging 22: 323‐332, 2001.
 78. Herman JP , McKlveen JM , Solomon MB , Carvalho‐Netto E , Myers B . Neural regulation of the stress response: Glucocorticoid feedback mechanisms. Braz J Med Biol Res 45: 292‐298, 2012.
 79. Herman JP , Ostrander MM , Mueller NK , Figueiredo H . Limbic system mechanisms of stress regulation: Hypothalamo‐pituitary‐adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29: 1201‐1213, 2005.
 80. Herman JP , Watson SJ , Spencer RL . Defense of adrenocorticosteroid receptor expression in rat hippocampus: Effects of stress and strain. Endocrinology 140: 3981‐3991, 1999.
 81. Hewitt SA , Wamsteeker JI , Kurz EU , Bains JS . Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis. Nat Neurosci 12: 438‐443, 2009.
 82. Hokfelt T . Neuropeptides in perspective: The last ten years. Neuron 7: 867‐879, 1991.
 83. Hrabovszky E , Liposits Z . Novel aspects of glutamatergic signalling in the neuroendocrine system. J Neuroendocrinol 20: 743‐751, 2008.
 84. Issa AM , Rowe W , Gauthier S , Meaney MJ . Hypothalamic‐pituitary‐adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J Neurosci 10: 3247‐3254, 1990.
 85. Jacobson L . Hypothalamic‐pituitary‐adrenocortical axis regulation. Endocrinol Metab Clin North Am 34: 271‐292, vii, 2005.
 86. Jacobson L , Muglia LJ , Weninger SC , Pacak K , Majzoub JA . CRH deficiency impairs but does not block pituitary‐adrenal responses to diverse stressors. Neuroendocrinology 71: 79‐87, 2000.
 87. Jankord R , Zhang R , Flak JN , Solomon MB , Albertz J , Herman JP . Stress activation of IL‐6 neurons in the hypothalamus. Am J Physiol Regul Integr Comp Physiol 299: R343‐R351, 2010.
 88. Jasper MS , Engeland WC . Splanchnicotomy increases adrenal sensitivity to ACTH in nonstressed rats. Am J Physiol 273: E363‐E368, 1997.
 89. Jenks BG . Regulation of proopiomelanocortin gene expression: An overview of the signaling cascades, transcription factors, and responsive elements involved. Ann N Y Acad Sci 1163: 17‐30, 2009.
 90. Jones KR , Myers B , Herman JP . Stimulation of the prelimbic cortex differentially modulates neuroendocrine responses to psychogenic and systemic stressors. Physiol Behav 104: 266‐271, 2011.
 91. Kajantie E , Phillips DI . The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31: 151‐178, 2006.
 92. Kalsbeek A , van der Spek R , Lei J , Endert E , Buijs RM , Fliers E . Circadian rhythms in the hypothalamo‐pituitary‐adrenal (HPA) axis. Mol Cell Endocrinol 349: 20‐29, 2012.
 93. Keller‐Wood M , Dallman MF . Corticosteroid inhibition of ACTH secretion. Endocrine Rev 5: 1‐24, 1984.
 94. Kirschbaum C , Kudielka BM , Gaab J , Schommer NC , Hellhammer DH . Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus‐pituitary‐adrenal axis. Psychosom Med 61: 154‐162, 1999.
 95. Koolhaas JM , Korte SM , De Boer SF , Van Der Vegt BJ , Van Reenen CG , Hopster H , De Jong IC , Ruis MA , Blokhuis HJ . Coping styles in animals: Current status in behavior and stress‐physiology. Neurosci Biobehav Rev 23: 925‐935, 1999.
 96. Ladd CO , Huot RL , Thrivikraman KV , Nemeroff CB , Meaney MJ , Plotsky PM . Long‐term behavioral and neuroendocrine adaptations to adverse early experience. Prog Brain Res 122: 81‐103, 2000.
 97.Le Minh N , Damiola F , Tronche F , Schutz G , Schibler U . Glucocorticoid hormones inhibit food‐induced phase‐shifting of peripheral circadian oscillators. EMBO J 20: 7128‐7136, 2001.
 98. Leal AM , Moreira AC . Food and the circadian activity of the hypothalamic‐pituitary‐adrenal axis. Braz J Med Biol Res 30: 1391‐1405, 1997.
 99. Li G , Cherrier MM , Tsuang DW , Petrie EC , Colasurdo EA , Craft S , Schellenberg GD , Peskind ER , Raskind MA , Wilkinson CW . Salivary cortisol and memory function in human aging. Neurobiol Aging 27: 1705‐1714, 2006.
 100. Lightman SL , Wiles CC , Atkinson HC , Henley DE , Russell GM , Leendertz JA , McKenna MA , Spiga F , Wood SA , Conway‐Campbell BL . The significance of glucocorticoid pulsatility. Eur J Pharmacol 583: 255‐262, 2008.
 101. Lilly MP , Engeland WC , Gann DS . Responses of cortisol secretion to repeated hemorrhage in the anesthetized dog. Endocrinology 112: 681‐688, 1983.
 102. Lilly MP , Engeland WC , Gann DS . Pituitary‐adrenal responses to repeated small hemorrhage in conscious dogs. Am J Physiol 251: R1200‐R1207, 1986.
 103. Liu D , Diorio J , Tannenbaum B , Caldji C , Francis D , Freedman A , Sharma S , Pearson D , Plotsky PM , Meaney MJ . Maternal care, hippocampal glucocorticoid receptors, and hypothalamic‐pituitary‐adrenal responses to stress [see comments]. Science 277: 1659‐1662, 1997.
 104. Lupien SJ , McEwen BS , Gunnar MR , Heim C . Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10: 434‐445, 2009.
 105. Makara GB , Stark E , Karteszi M , Palkovits M , Rappay G . Effects of paraventricular lesions on stimulated ACTH release and CRF in stalk‐median eminence of the rat. Am J Physiol 240: E441‐E446, 1981.
 106. Makino S , Gold PW , Schulkin J . Corticosterone effects on corticotropin‐releasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus. Brain Res 640: 105‐112, 1994.
 107. Makino S , Gold PW , Schulkin J . Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 657: 141‐149, 1994.
 108. Makino S , Shibasaki T , Yamauchi N , Nishioka T , Mimoto T , Wakabayashi I , Gold PW , Hashimoto K . Psychological stress increased corticotropin‐releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat. Brain Res 850: 136‐143, 1999.
 109. Marti O , Armario A . Anterior pituitary response to stress: Time‐related changes and adaptation. Int J Dev Neurosci 16: 241‐260, 1998.
 110. Mayberg HS , Lozano AM , Voon V , McNeely HE , Seminowicz D , Hamani C , Schwalb JM , Kennedy SH . Deep brain stimulation for treatment‐resistant depression. Neuron 45: 651‐660, 2005.
 111. McKlveen JM , Myers B , Flak JN , Bundzikova J , Solomon MB , Seroogy KB , Herman JP . Role of prefrontal cortex glucocorticoid receptors in stress and emotion. Biol Psychiatry 74: 672‐679, 2013.
 112. Merighi A . Costorage and coexistence of neuropeptides in the mammalian CNS. Prog Neurobiol 66: 161‐190, 2002.
 113. Moisan MP , Minni AM , Dominguez G , Helbling JC , Foury A , Henkous N , Dorey R , Beracochea D . Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain. Steroids 81: 109‐115, 2014.
 114. Muglia LJ , Jacobson L , Weninger SC , Karalis KP , Jeong K , Majzoub JA . The physiology of corticotropin‐releasing hormone deficiency in mice. Peptides 22: 725‐731, 2001.
 115. Murakami K , Nakagawa T , Shozu M , Uchide K , Koike K , Inoue M . Changes with aging of steroidal levels in the cerebrospinal fluid of women. Maturitas 33: 71‐80, 1999.
 116. Myers B , McKlveen JM , Herman JP . Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 35: 180‐196, 2014.
 117. Myers B , McKlveen JM , Herman JP . Neural regulation of the stress response: The many faces of feedback. Cell Mol Neurobiol 352: 683‐596, 2012.
 118. Nahar J , Haam J , Chen C , Jiang Z , Glatzer NR , Muglia LJ , Dohanich GP , Herman JP , Tasker JG . Rapid nongenomic glucocorticoid actions in male mouse hypothalamic neuroendocrine cells are dependent on the nuclear glucocorticoid receptor. Endocrinology 156: 2831‐2842, 2015.
 119. Natelson BH , Ottenweller JE , Cook JA , Pitman D , McCarty R , Tapp WN . Effect of stressor intensity on habituation of the adrenocortical stress response. Physiol Behav 43: 41‐46, 1988.
 120. Nederhof E , Schmidt MV . Mismatch or cumulative stress: Toward an integrated hypothesis of programming effects. Physiol Behav 106: 691‐700, 2012.
 121. Ongur D , Price JL . The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10: 206‐219, 2000.
 122. Peters J , Kalivas PW , Quirk GJ . Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16: 279‐288, 2009.
 123. Purnell JQ , Brandon DD , Isabelle LM , Loriaux DL , Samuels MH . Association of 24‐hour cortisol production rates, cortisol‐binding globulin, and plasma‐free cortisol levels with body composition, leptin levels, and aging in adult men and women. J Clin Endocrinol Metab 89: 281‐287, 2004.
 124. Rabasa C , Munoz‐Abellan C , Daviu N , Nadal R , Armario A . Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic‐pituitary‐adrenal axis. Physiol Behav 103: 125‐133, 2011.
 125. Radley JJ , Arias CM , Sawchenko PE . Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress. J Neurosci 26: 12967‐12976, 2006.
 126. Radley JJ , Kabbaj M , Jacobson L , Heydendael W , Yehuda R , Herman JP . Stress risk factors and stress‐related pathology: Neuroplasticity, epigenetics and endophenotypes. Stress 14: 481‐497, 2011.
 127.Radley JJ, Arias CM, Sawchenko PE. Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress. J Neurosci 26: 12967‐12976, 2006.
 128. Radley JJ , Sawchenko PE . A common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response. J Neurosci 31: 9683‐9695, 2011.
 129. Raff H , Raff JL , Duthie EH , Wilson CR , Sasse EA , Rudman I , Mattson D . Elevated salivary cortisol in the evening in healthy elderly men and women: Correlation with bone mineral density. J Gerontol A Biol Sci Med Sci 54: M479‐M483, 1999.
 130. Raff H , Shinsako J , Dallman MF . Surgery potentiates adrenocortical responses to hypoxia in dogs. Proc Soc Exp Biol Med 172: 400‐406, 1983.
 131. Reber SO , Birkeneder L , Veenema AH , Obermeier F , Falk W , Straub RH , Neumann ID . Adrenal insufficiency and colonic inflammation after a novel chronic psycho‐social stress paradigm in mice: Implications and mechanisms. Endocrinology 148: 670‐682, 2007.
 132. Rivest S . How circulating cytokines trigger the neural circuits that control the hypothalamic‐pituitary‐adrenal axis. Psychoneuroendocrinology 26: 761‐788, 2001.
 133. Roca CA , Schmidt PJ , Deuster PA , Danaceau MA , Altemus M , Putnam K , Chrousos GP , Nieman LK , Rubinow DR . Sex‐related differences in stimulated hypothalamic‐pituitary‐adrenal axis during induced gonadal suppression. J Clin Endocrinol Metab 90: 4224‐4231, 2005.
 134. Romeo RD . Pubertal maturation and programming of hypothalamic‐pituitary‐adrenal reactivity. Front Neuroendocrinol 31: 232‐240, 2010.
 135. Russell GM , Kalafatakis K , Lightman SL . The importance of biological oscillators for HPA activity and tissue glucocorticoid response: Coordinating stress and neurobehavioural adaptation. J Neuroendocrinol 27: 378‐388, 2015.
 136. Sapolsky RM . Glucocorticoids and hippocampal damage. Trends Neurosci 10: 346‐349, 1987.
 137. Sapolsky RM . Do glucocorticoid concentrations rise with age in the rat? Neurobiol Aging 13: 171‐174, 1991.
 138. Sapolsky RM , Krey LC , McEwen BS . The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev 7: 284‐301, 1986.
 139. Sapolsky RM , Meaney MJ . Maturation of the adrenal stress response: Neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res Rev 11: 65‐76, 1986.
 140. Sawchenko PE , Li HY , Ericsson A . Circuits and mechanisms governing hypothalamic responses to stress: A tale of two paradigms. Prog Brain Res 122: 61‐78, 2000.
 141. Schotanus K , Tilders FJ , Berkenbosch F . Human recombinant interleukin‐1 receptor antagonist prevents adrenocorticotropin, but not interleukin‐6 responses to bacterial endotoxin in rats. Endocrinology 133: 2461‐2468, 1993.
 142. Schroeder RJ , Henning SJ . Roles of plasma clearance and corticosteroid‐binding globulin in the developmental increase in circulating corticosterone in infant rats. Endocrinology 124: 2612‐2618, 1989.
 143. Schwaber JS , Kapp BS , Higgins GA , Rapp PR . Amygdala and basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus. J Neurosci 2: 1424‐1438, 1982.
 144. Seckl JR . 11 beta‐hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation. Eur J Clin Invest 23: 589‐601, 1993.
 145. Seckl JR , Walker BR . Minireview: 11Beta‐hydroxysteroid dehydrogenase type 1 ‐ A tissue‐specific amplifier of glucocorticoid action. Endocrinology 142: 1371‐1376, 2001.
 146. Seeman TE , Singer B , Wilkinson CW , McEwen B . Gender differences in age‐related changes in HPA axis reactivity. Psychoneuroendocrinology 26: 225‐240, 2001.
 147. Segar TM , Kasckow JW , Welge JA , Herman JP . Heterogeneity of neuroendocrine stress responses in aging rat strains. Physiol Behav 96: 6‐11, 2009.
 148. Shin LM , Wright CI , Cannistraro PA , Wedig MM , McMullin K , Martis B , Macklin ML , Lasko NB , Cavanagh SR , Krangel TS , Orr SP , Pitman RK , Whalen PJ , Rauch SL . A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62: 273‐281, 2005.
 149. Simpson ER , Waterman MR . Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 50: 427‐440, 1988.
 150. Soares JM , Sampaio A , Ferreira LM , Santos NC , Marques F , Palha JA , Cerqueira JJ , Sousa N . Stress‐induced changes in human decision‐making are reversible. Transl Psychiatry 2: e131, 2012.
 151. Solomon MB , Furay AR , Jones K , Packard AE , Packard BA , Wulsin AC , Herman JP . Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression‐like behavior in males but not females. Neuroscience 203: 135‐143, 2012.
 152. Solomon MB , Jones K , Packard BA , Herman JP . The medial amygdala modulates body weight but not neuroendocrine responses to chronic stress. J Neuroendocrinol 22: 13‐23, 2010.
 153. Solomon MB , Loftspring M , de Kloet AD , Ghosal S , Jankord R , Flak JN , Wulsin AC , Krause EG , Zhang R , Rice T , McKlveen J , Myers B , Tasker JG , Herman JP . Neuroendocrine function after hypothalamic depletion of glucocorticoid receptors in male and female mice. Endocrinology 156: 2843‐2853, 2015.
 154. Son SJ , Filosa JA , Potapenko ES , Biancardi VC , Zheng H , Patel KP , Tobin VA , Ludwig M , Stern JE . Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron 78: 1036‐1049, 2013.
 155. Spencer RL , Miller AH , Moday H , McEwen BS , Blanchard RJ , Blanchard DC , Sakai RR . Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels. Psychoneuroendocrinology 21: 95‐109, 1996.
 156. Spiess J , Rivier J , Rivier C , Vale W . Primary structure of corticotropin‐releasing factor from ovine hypothalamus. Proc Natl Acad Sci U S A 78: 6517‐6521, 1981.
 157. Sullivan RM , Gratton A . Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J Neurosci 19: 2834‐2840, 1999.
 158. Tavares RF , Correa FM , Resstel LB . Opposite role of infralimbic and prelimbic cortex in the tachycardiac response evoked by acute restraint stress in rats. J Neurosci Res 87: 2601‐2607, 2009.
 159. Tinnikov AA . Responses of serum corticosterone and corticosteroid‐binding globulin to acute and prolonged stress in the rat. Endocrine 11: 145‐150, 1999.
 160. Turnbull AV , Rivier CL . Sprague‐Dawley rats obtained from different vendors exhibit distinct adrenocorticotropin responses to inflammatory stimuli. Neuroendocrinology 70: 186‐195, 1999.
 161. Ulrich‐Lai YM , Engeland WC . Adrenal splanchnic innervation modulates adrenal cortical responses to dehydration stress in rats. Neuroendocrinology 76: 79‐92, 2002.
 162. Ulrich‐Lai YM , Figueiredo HF , Ostrander MM , Choi DC , Engeland WC , Herman JP . Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion‐specific manner. Am J Physiol Endocrinol Metab 291: E965‐E973, 2006.
 163. Ulrich‐Lai YM , Herman JP . Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10: 397‐409, 2009.
 164. Ulrich‐Lai YM , Jones KR , Ziegler DR , Cullinan WE , Herman JP . Forebrain origins of glutamatergic innervation to the rat paraventricular nucleus of the hypothalamus: differential inputs to the anterior versus posterior subregions. J Comp Neurol 519: 1301‐1319, 2011.
 165. Ulrich‐Lai YM , Ostrander MM , Thomas IM , Packard BA , Furay AR , Dolgas CM , Van Hooren DC , Figueiredo HF , Mueller NK , Choi DC , Herman JP . Daily limited access to sweetened drink attenuates hypothalamic‐pituitary‐adrenocortical axis stress responses. Endocrinology 148: 1823‐1834, 2007.
 166. Ulrich‐Lai YM , Xie W , Meij JT , Dolgas CM , Yu L , Herman JP . Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav 88: 67‐76, 2006.
 167. Vahl TP , Ulrich‐Lai YM , Ostrander MM , Dolgas CM , Elfers EE , Seeley RJ , D'Alessio DA , Herman JP . Comparative analysis of ACTH and corticosterone sampling methods in rats. Am J Physiol Endocrinol Metab 289: E823‐E828, 2005.
 168. Vamvakopoulos NV . Sexual dimorphism of stress response and immune/inflammatory reaction: the corticotropin releasing hormone perspective. Mediators Inflamm 4: 163‐174, 1995.
 169. van Ast VA , Cornelisse S , Meeter M , Joels M , Kindt M . Time‐dependent effects of cortisol on the contextualization of emotional memories. Biol Psychiatry 74: 809‐816, 2013.
 170. Vertes RP . Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51: 32‐58, 2004.
 171. Viau V , Meaney MJ . Variations in the hypothalamic‐pituitary‐adrenal response to stress during the estrous cycle in the rat. Endocrinology 129: 2503‐2511, 1991.
 172. Viau V , Meaney MJ . The inhibitory effect of testosterone on hypothalamo‐pituitary‐adrenal responses to stress is mediated by the medial preoptic area. J Neurosci 16: 1866‐1876, 1996.
 173. Walker AK , Nakamura T , Byrne RJ , Naicker S , Tynan RJ , Hunter M , Hodgson DM . Neonatal lipopolysaccharide and adult stress exposure predisposes rats to anxiety‐like behaviour and blunted corticosterone responses: Implications for the double‐hit hypothesis. Psychoneuroendocrinology 34: 1515‐1525, 2009.
 174. Weaver IC , Cervoni N , Champagne FA , D'Alessio AC , Sharma S , Seckl JR , Dymov S , Szyf M , Meaney MJ . Epigenetic programming by maternal behavior. Nat Neurosci 7: 847‐854, 2004.
 175. Weiss EL , Longhurst JG , Mazure CM . Childhood sexual abuse as a risk factor for depression in women: Psychosocial and neurobiological correlates. Am J Psychiatry 156: 816‐828, 1999.
 176. Wilkinson CW , Peskind ER , Raskind MA . Decreased hypothalamic‐pituitary‐adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology 65: 79‐90, 1997.
 177. Wilkinson CW , Petrie EC , Murray SR , Colasurdo EA , Raskind MA , Peskind ER . Human glucocorticoid feedback inhibition is reduced in older individuals: Evening study. J Clin Endocrinol Metab 86: 545‐550, 2001.
 178. Ziegler DR , Edwards MR , Ulrich‐Lai YM , Herman JP , Cullinan WE . Brainstem origins of glutamatergic innervation of the rat hypothalamic paraventricular nucleus. J Comp Neurol 520: 2369‐2394, 2012.
 179. Zohar J , Yahalom H , Kozlovsky N , Cwikel‐Hamzany S , Matar MA , Kaplan Z , Yehuda R , Cohen H . High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies. Eur Neuropsychopharmacol 21: 796‐809, 2011.

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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Article Title: Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response
 

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, null: 603-621. doi: 10.1002/cphy.c150015