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Neural regulation of endocrine and autonomic stress responses
Nature Reviews Neurosciencevolume 10, pages397–409 (2009)Cite this article
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Key Points
The response of mammals to external or internal challenge involves engagement of multiple physiological systems, prominently including the hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system (ANS).
Autonomic and HPA axis responses to systemic stressors are initiated by brainstem and hypothalamic structures that receive direct and indirect homeostatic feedback.
Psychological stress responses are activated and inhibited by limbic system structures, such as the medial prefrontal cortex, the hippocampus and the amygdala, which send multisynaptic input to brainstem and hypothalamic activators of the HPA axis and the ANS.
'Psychological' information and homeostatic information are integrated by telencephalic and diencephalic relays prior to the elaboration of HPA axis or ANS responses.
HPA axis and ANS components of the stress response are probably encoded in distinct yet highly interconnected limbic subregions.
Chronic stress induces neuroplasticity in central stress-processing networks, causing sensitization as well as habituation of HPA axis and ANS responses.
Limbic stress response networks overlap extensively with memory and reward circuitry, allowing stress responses to be coloured by prior experience and expected outcomes.
Abstract
The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re-establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.
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References
Iversen, S., Iversen, L. & Saper, C. B. inPrinciples of Neural Science (eds Kandel, E. R., Schwartz, J. H. & Jessell, T. M.) (McGraw-Hill, New York, 2000).
Droste, S. K. et al. Corticosterone levels in the brain show a distinct ultradian rhythm but a delayed response to forced swim stress.Endocrinology149, 3244–3253 (2008).
Herman, J. P. et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.Front. Neuroendocrinol.24, 151–180 (2003).
Cunningham, E. T. Jr, Bohn, M. C. & Sawchenko, P. E. Organization of adrenergic inputs to the paraventricular and supraoptic nuclei of the hypothalamus in the rat.J. Comp. Neurol.292, 651–667 (1990).
Cunningham, E. T. Jr & Sawchenko, P. E. Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus.J. Comp. Neurol.274, 60–76 (1988).
Plotsky, P. M., Cunningham, E. T. Jr & Widmaier, E. P. Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion.Endocr. Rev.10, 437–458 (1989).An excellent review of a large body of work on catecholaminergic regulation of the HPA axis.
Hokfelt, T. et al. Coexistence of peptides with classical transmitters.Experientia43, 768–780 (1987).
Larsen, P. J., Tang-Christensen, M., Holst, J. J. & Orskov, C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem.Neuroscience77, 257–270 (1997).
Sawchenko, P. E., Arias, C. & Bittencourt, J. C. Inhibin beta, somatostatin and enkephalin immunoreactivities coexist in caudal medullary neurons that project to the paraventricular nucleus of the hypothalamus.J. Comp. Neurol.291, 269–280 (1990).
Buller, K., Xu, Y., Dayas, C. & Day, T. Dorsal and ventral medullary catecholamine cell groups contribute differentially to systemic interleukin-1β-induced hypothalamic pituitary adrenal axis responses.Neuroendocrinology73, 129–138 (2001).
Ritter, S., Watts, A. G., Dinh, T. T., Sanchez-Watts, G. & Pedrow, C. Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion.Endocrinology144, 1357–1367 (2003).Used a selective lesion method to establish clear differences in the role of the nucleus of the solitary tract noradrenaline and adrenaline pathways in the regulation of homeostatic versus psychological stressors.
Kinzig, K. P. et al. CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors.J. Neurosci.23, 6163–6170 (2003).
Lowry, C. A. Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis.J. Neuroendocrinol.14, 911–923 (2002).
Zhang, Y. et al. Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (–) DOI.J. Neurosci.22, 9635–9642 (2002).
Sawchenko, P. E., Swanson, L. W., Steinbusch, H. W. & Verhofstad, A. A. The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat.Brain Res.277, 355–360 (1983).
Krause, E. G. et al. Angiotensin type 1 receptors in the subfornical organ mediate the drinking and hypothalamic-pituitary-adrenal response to systemic isoproterenol.Endocrinology149, 6416–6424 (2008).
Plotsky, P. M., Sutton, S. W., Bruhn, T. O. & Ferguson, A. V. Analysis of the role of angiotensin II in mediation of adrenocorticotropin secretion.Endocrinology122, 538–545 (1988).
Swanson, L. W. & Lind, R. W. Neural projections subserving the initiation of a specific motivated behavior in the rat: new projections from the subfornical organ.Brain Res.379, 399–403 (1986).
Johnson, A. K., Cunningham, J. T. & Thunhorst, R. L. Integrative role of the lamina terminalis in the regulation of cardiovascular and body fluid homeostasis.Clin. Exp. Pharmacol. Physiol.23, 183–191 (1996).
Swanson, L. W. & Kuypers, H. G. The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods.J. Comp. Neurol.194, 555–570 (1980).
Kreier, F. et al. Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes.Endocrinology147, 1140–1147 (2006).
Decavel, C. & Van Den Pol, A. N. GABA: a dominant neurotransmitter in the hypothalamus.J. Comp. Neurol.302, 1019–1037 (1990).
Cole, R. L. & Sawchenko, P. E. Neurotransmitter regulation of cellular activation and neuropeptide gene expression in the paraventricular nucleus of the hypothalamus.J. Neurosci.22, 959–969 (2002).
Park, J. B., Skalska, S., Son, S. & Stern, J. E. Dual GABAA receptor-mediated inhibition in rat presympathetic paraventricular nucleus neurons.J. Physiol.582, 539–551 (2007).
Roland, B. L. & Sawchenko, P. E. Local origins of some GABAergic projections to the paraventricular and supraoptic nuclei of the hypothalamus of the rat.J. Comp. Neurol.332, 123–143 (1993).
Herman, J. P., Cullinan, W. E., Ziegler, D. R. & Tasker, J. G. Role of the paraventricular nucleus microenvironment in stress integration.Eur. J. Neurosci.16, 381–385 (2002).
Bailey, T. W. & Dimicco, J. A. Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in conscious rats.Am. J. Physiol. Regul. Integr. Comp. Physiol.280, R8–R15 (2001).
Stotz-Potter, E. H., Willis, L. R. & DiMicco, J. A. Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress.J. Neurosci.16, 1173–1179 (1996).One of several excellent papers from the DiMicco laboratory demonstrating the importance of the DMH in stress regulation. This study used a microinjection strategy to prove the primacy of the DMH in regulating cardiovascular stress responses. See other papers from this group for more information.
Curran, T. et al. Inducible proto-oncogene transcription factors: third messengers in the brain?Cold Spring Harb. Symp. Quant. Biol.55, 225–234 (1990).
DiMicco, J. A., Samuels, B. C., Zaretskaia, M. V. & Zaretsky, D. V. The dorsomedial hypothalamus and the response to stress: part renaissance, part revolution.Pharmacol. Biochem. Behav.71, 469–480 (2002).
Cullinan, W. E., Helmreich, D. L. & Watson, S. J. Fos expression in forebrain afferents to the hypothalamic paraventricular nucleus following swim stress.J. Comp. Neurol.368, 88–99 (1996).
Davis, M. The role of the amygdala in fear and anxiety.Annu. Rev. Neurosci.15, 353–375 (1992).
Sawchenko, P. E. et al. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress.Prog. Brain Res.107, 201–222 (1996).
Sawchenko, P. E., Li, H. Y. & Ericsson, A. Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms.Prog. Brain Res.122, 61–78 (2000).A review that highlights groundbreaking work from the Sawchenko laboratory, summarizing studies that demonstrate stressor specificity in central neurocircuit activation.
Xu, Y., Day, T. A. & Buller, K. M. The central amygdala modulates hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1β administration.Neuroscience94, 175–183 (1999).
Dayas, C. V., Buller, K. M. & Day, T. A. Neuroendocrine responses to an emotional stressor: evidence for involvement of the medial but not the central amygdala.Eur. J. Neurosci.11, 2312–2322 (1999).
Prewitt, C. M. & Herman, J. P. Hypothalamo-pituitary-adrenocortical regulation following lesions of the central nucleus of the amygdala.Stress1, 263–280 (1997).
Roozendaal, B., Koolhaas, J. M. & Bohus, B. Differential effect of lesioning of the central amygdala on the bradycardiac and behavioral response of the rat in relation to conditioned social and solitary stress.Behav. Brain Res.41, 39–48 (1990).
Roozendaal, B., Koolhaas, J. M. & Bohus, B. Central amygdala lesions affect behavioral and autonomic balance during stress in rats.Physiol. Behav.50, 777–781 (1991).
Cullinan, W. E., Herman, J. P., Battaglia, D. F., Akil, H. & Watson, S. J. Pattern and time course of immediate early gene expression in rat brain following acute stress.Neuroscience64, 477–505 (1995).
Dayas, C. V., Buller, K. M., Crane, J. W., Xu, Y. & Day, T. A. 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).A key paper from the Day laboratory, demonstrating that lesions of the MeA but not the CeA block ACTH responses and PVN activation by psychogenic stress.
Bhatnagar, S., Vining, C. & Denski, K. Regulation of chronic stress-induced changes in hypothalamic-pituitary-adrenal activity by the basolateral amygdala.Ann. NY Acad. Sci.1032, 315–319 (2004).
Prewitt, C. M. & Herman, J. P. Anatomical interactions between the central amygdaloid nucleus and the hypothalamic paraventricular nucleus of the rat: a dual tract-tracing analysis.J. Chem. Neuroanat.15, 173–185 (1998).
Jacobson, L. & Sapolsky, R. M. The role of the hippocampus in feedback regulation of the hypothalamo-pituitary-adrenocortical axis.Endocr. Rev.12, 118–134 (1991).
Rubin, R. T., Mandell, A. J. & Crandall, P. H. Corticosteroid responses to limbic stimulation in man: localization of stimulation sites.Science153, 1212–1215 (1966).
Dunn, J. D. & Orr, S. E. Differential plasma corticosterone responses to hippocampal stimulation.Exp. Brain Res.54, 1–6 (1984).
Herman, J. P. & Mueller, N. K. Role of the ventral subiculum in stress integration.Behav. Brain Res.174, 215–224 (2006).
Ruit, K. G. & Neafsey, E. J. Cardiovascular and respiratory responses to electrical and chemical stimulation of the hippocampus in anesthetized and awake rats.Brain Res.457, 310–321 (1988).
Ruit, K. G. & Neafsey, E. J. Hippocampal input to a “visceral motor” corticobulbar pathway: an anatomical and electrophysiological study in the rat.Exp. Brain Res.82, 606–616 (1990).
Figueiredo, H. F., Bruestle, A., Bodie, B., Dolgas, C. M. & Herman, J. P. 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).
Diorio, D., Viau, V. & Meaney, M. J. 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).
Radley, J. J., Arias, C. M. & Sawchenko, P. E. Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress.J. Neurosci.26, 12967–12976 (2006).The most recent paper on the role of the medial prefrontal cortex in stress regulation, showing differential actions of the dorsal and the ventromedial prefrontal cortex in HPA axis inhibition and activation of PVN preautonomic neurons, respectively.
Gerrits, M. et al. Increased stress vulnerability after a prefrontal cortex lesion in female rats.Brain Res. Bull.61, 627–635 (2003).
Akana, S. F., Chu, A., Soriano, L. & Dallman, M. F. Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots.J. Neuroendocrinol.13, 625–637 (2001).
Sullivan, R. M. & Gratton, A. Behavioral effects of excitotoxic lesions of ventral medial prefrontal cortex in the rat are hemisphere-dependent.Brain Res.927, 69–79 (2002).
Frysztak, R. J. & Neafsey, E. J. The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat.Brain Res.643, 181–193 (1994).
Resstel, L. B., Joca, S. R., Guimaraes, F. G. & Correa, F. M. Involvement of medial prefrontal cortex neurons in behavioral and cardiovascular responses to contextual fear conditioning.Neuroscience143, 377–385 (2006).
Resstel, L. B., Fernandes, K. B. & Correa, F. M. Medial prefrontal cortex modulation of the baroreflex parasympathetic component in the rat.Brain Res.1015, 136–144 (2004).
Dobrakovova, M., Kvetnansky, R., Torda, T. & Murgas, K. Changes of plasma and adrenal catecholamines and corticosterone in stressed rats with septal lesions.Physiol. Behav.29, 41–45 (1982).
Suarez, M., Maglianesi, M. A. & Perassi, N. I. Involvement of the anterodorsal thalami nuclei on the hypophysoadrenal response to chronic stress in rats.Physiol. Behav.64, 111–116 (1998).
Han, F., Ozawa, H., Matsuda, K., Nishi, M. & Kawata, M. Colocalization of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus and hypothalamus.Neurosci. Res.51, 371–381 (2005).
De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S. & Joels, M. Brain corticosteroid receptor balance in health and disease.Endocr. Rev.19, 269–301 (1998).
Boyle, M. P. et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior.Proc. Natl Acad. Sci. USA102, 473–478 (2005).Used a region-specific knockout mouse to indicate the requirement of the hippocampal and cortical GR in normal stress termination and glucocorticoid negative feedback.
Furay, A. R., Bruestle, A. E. & Herman, J. P. The role of the forebrain glucocorticoid receptor in acute and chronic stress.Endocrinology149, 5482–5490 (2008).
Wei, Q. et al. Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction.J. Neurosci.27, 8836–8844 (2007).
Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability.Proc. Natl Acad. Sci. USA101, 11851–11856 (2004).
Berger, S. et al. Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity.Proc. Natl Acad. Sci. USA103, 195–200 (2006).
Rozeboom, A. M., Akil, H. & Seasholtz, A. F. Mineralocorticoid receptor overexpression in forebrain decreases anxiety-like behavior and alters the stress response in mice.Proc. Natl Acad. Sci. USA104, 4688–4693 (2007).
Swanson, L. W. & Petrovich, G. D. What is the amygdala?Trends Neurosci.21, 323–331 (1998).
Schwaber, J. S., Kapp, B. S., Higgins, G. A. & Rapp, P. R. Amygdala and basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus.J. Neurosci.2, 1424–1438 (1982).
van der Kooy, D., Koda, L. Y., McGinty, J. F., Gerfen, C. R. & Bloom, F. E. The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat.J. Comp. Neurol.224, 1–24 (1984).
Choi, D. C. et al. 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).A paper from our group demonstrating selective involvement of distinct BST cell populations in activation and inhibition of HPA axis stress responses.
Gray, T. S. et al. Ibotenic acid lesions in the bed nucleus of the stria terminalis attenuate conditioned stress-induced increases in prolactin, ACTH and corticosterone.Neuroendocrinology57, 517–524 (1993).
Dong, H. W., Petrovich, G. D., Watts, A. G. & Swanson, L. W. Basic organization of projections from the oval and fusiform nuclei of the bed nuclei of the stria terminalis in adult rat brain.J. Comp. Neurol.436, 430–455 (2001).
Champagne, D., Beaulieu, J. & Drolet, G. CRFergic innervation of the paraventricular nucleus of the rat hypothalamus: a tract-tracing study.J. Neuroendocrinol.10, 119–131 (1998).
Cullinan, W. E., Herman, J. P. & Watson, S. J. 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).This study used dual tracing methods to demonstrate innervation of PVN-projecting neurons by ventral subiculum (that is, hippocampal) efferents. It also documented the predominantly GABAergic phenotype of most PVN-projecting regions in the BST.
Ciriello, J. & Janssen, S. A. Effect of glutamate stimulation of bed nucleus of the stria terminalis on arterial pressure and heart rate.Am. J. Physiol.265, H1516–H1522 (1993).
Gelsema, A. J. & Calaresu, F. R. Chemical microstimulation of the septal area lowers arterial pressure in the rat.Am. J. Physiol.252, R760–R767 (1987).
Hatam, M. & Nasimi, A. Glutamatergic systems in the bed nucleus of the stria terminalis, effects on cardiovascular system.Exp. Brain Res.178, 394–401 (2007).
Alves, F. H., Crestani, C. C., Resstel, L. B. & Correa, F. M. Cardiovascular effects of carbachol microinjected into the bed nucleus of the stria terminalis of the rat brain.Brain Res.1143, 161–168 (2007).
Crestani, C. C., Alves, F. H., Resstel, L. B. & Correa, F. M. Both α1 and α2-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the bed nucleus of the stria terminal of rats.Br. J. Pharmacol.153, 583–590 (2008).
Crestani, C. C., Alves, F. H., Tavares, R. F. & Correa, F. M. Role of the bed nucleus of the stria terminalis in the cardiovascular responses to acute restraint stress in rats.Stress 10 Oct 2008 (doi:10.1080/10253890802331477).
Viau, V. & Meaney, M. J. 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).
Zaretsky, D. V., Hunt, J. L., Zaretskaia, M. V. & DiMicco, J. A. Microinjection of prostaglandin E2 and muscimol into the preoptic area in conscious rats: comparison of effects on plasma adrenocorticotrophic hormone (ACTH), body temperature, locomotor activity, and cardiovascular function.Neurosci. Lett.397, 291–296 (2006).
Feldman, S., Conforti, N. & Saphier, D. The preoptic area and bed nucleus of the stria terminalis are involved in the effects of the amygdala on adrenocortical secretion.Neuroscience37, 775–779 (1990).
Swanson, L. W. inHandbook of Chemical Neuroanatomy (eds Björklund, A., Hökfelt, T. & Swanson, L. W.) 1–124 (Elsevier, Amsterdam, 1987).
Canteras, N. S., Simerly, R. B. & Swanson, L. W. Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat.J. Comp. Neurol.360, 213–245 (1995).
Sawchenko, P. E. Toward a new neurobiology of energy balance, appetite, and obesity: the anatomists weigh in.J. Comp. Neurol.402, 435–441 (1998).
Woods, S. C. The eating paradox: how we tolerate food.Psychol. Rev.98, 488–505 (1991).
Swanson, L. W., Sanchez-Watts, G. & Watts, A. G. Comparison of melanin-concentrating hormone and hypocretin/orexin mRNA expression patterns in a new parceling scheme of the lateral hypothalamic zone.Neurosci. Lett.387, 80–84 (2005).
Ziegler, D. R., Cullinan, W. E. & Herman, J. P. Distribution of vesicular glutamate transporter mRNA in rat hypothalamus.J. Comp. Neurol.448, 217–229 (2002).
Cascio, C. S., Shinsako, J. & Dallman, M. F. The suprachiasmatic nuclei stimulate evening ACTH secretion in the rat.Brain Res.423, 173–178 (1987).
Kalsbeek, A., La Fleur, S., Van Heijningen, C. & Buijs, R. M. Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver.J. Neurosci.24, 7604–7613 (2004).
Buijs, R. M., Wortel, J., Van Heerikhuize, J. J. & Kalsbeek, A. Novel environment induced inhibition of corticosterone secretion: physiological evidence for a suprachiasmatic nucleus mediated neuronal hypothalamo-adrenal cortex pathway.Brain Res.758, 229–236 (1997).
Watts, A. G., Swanson, L. W. & Sanchez-Watts, G. Efferent projections of the suprachiasmatic nucleus: studies using anterograde transport ofPhaseolus vulgaris leucoagglutinin in the rat.J. Comp. Neurol.258, 204–229 (1987).
Magarinos, A. M. & McEwen, B. S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors.Neuroscience69, 89–98 (1995).One of an excellent series of papers from the McEwen group demonstrating the ability of stress to alter the structure of hippocampal neurons. Knowledge of this subject is vital for understanding potential mechanisms of chronic stress-induced plasticity of stress circuitry.
Radley, J. J. et al. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex.J. Comp. Neurol.507, 1141–1150 (2008).
Vyas, A., Mitra, R., Shankaranarayana Rao, B. S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.J. Neurosci.22, 6810–6818 (2002).
Herman, J. P., Adams, D. & Prewitt, C. M. Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm.Neuroendocrinology61, 180–190 (1995).
Makino, S., Smith, M. A. & Gold, P. W. Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels.Endocrinology136, 3299–3309 (1995).
Cullinan, W. E. GABAA receptor subunit expression within hypophysiotropic CRH neurons: a dual hybridization histochemical study.J. Comp. Neurol.419, 344–351 (2000).
Ziegler, D. R., Cullinan, W. E. & Herman, J. P. Organization and regulation of paraventricular nucleus glutamate signaling systems:N-methyl-D-aspartate receptors.J. Comp. Neurol.484, 43–56 (2005).
Bowers, G., Cullinan, W. E. & Herman, J. P. Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits.J. Neurosci.18, 5938–5947 (1998).
Akana, S. F. et al. Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress.Endocrinology131, 57–68 (1992).
Ulrich-Lai, Y. M. et al. Daily limited access to sweetened drink attenuates hypothalamic-pituitary-adrenocortical axis stress responses.Endocrinology148, 1823–1834 (2007).
Bhatnagar, S. & Dallman, M. Neuroanatomical basis for facilitation of hypothalamic-pituitary- adrenal responses to a novel stressor after chronic stress.Neuroscience84, 1025–1039 (1998).The first paper to document possible neural mechanisms of chronic stress facilitation of HPA axis stress responses.
Choi, D. C. et al. The anteroventral bed nucleus of the stria terminalis differentially regulates hypothalamic-pituitary-adrenocortical axis responses to acute and chronic stress.Endocrinology149, 818–826 (2008).
Nisenbaum, L. K. & Abercrombie, E. D. Presynaptic alterations associated with enhancement of evoked release and synthesis of norepinephrine in hippocampus of chronically cold-stressed rats.Brain Res.608, 280–287 (1993).
Jedema, H. P., Finlay, J. M., Sved, A. F. & Grace, A. A. Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locus coeruleus neurons.Biol. Psychiatry49, 351–359 (2001).
Mana, M. J. & Grace, A. A. Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons.Neuroscience81, 1055–1064 (1997).
Holmes, P. V., Blanchard, D. C., Blanchard, R. J., Brady, L. S. & Crawley, J. N. Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus.Pharmacol. Biochem. Behav.50, 655–660 (1995).
Watanabe, Y. et al. Effects of chronic social stress on tyrosine hydroxylase mRNA and protein levels.Brain Res. Mol. Brain Res.32, 176–180 (1995).
Smith, M. A., Brady, L. S., Glowa, J., Gold, P. W. & Herkenham, M. Effects of stress and adrenalectomy on tyrosine hydroxylase mRNA levels in locus coeruleus byin situ hybridization.Brain Res.544, 26–32 (1991).
Makino, S., Gold, P. W. & 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).
Ulrich-Lai, Y. M. et al. Limbic and HPA axis function in an animal model of chronic neuropathic pain.Physiol. Behav.88, 67–76 (2006).
Figueiredo, H. F., Bodie, B. L., Tauchi, M., Dolgas, C. M. & Herman, J. P. Stress integration after acute and chronic predator stress: differential activation of central stress circuitry and sensitization of the hypothalamo-pituitary-adrenocortical axis.Endocrinology144, 5249–5258 (2003).
Cook, C. J. Stress induces CRF release in the paraventricular nucleus, and both CRF and GABA release in the amygdala.Physiol. Behav.82, 751–762 (2004).
Cook, C. J. Glucocorticoid feedback increases the sensitivity of the limbic system to stress.Physiol. Behav.75, 455–464 (2002).
Gomez, F., Lahmame, A., de Kloet, E. R. & Armario, A. Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: differential responses are mainly located at the adrenocortical level.Neuroendocrinology63, 327–337 (1996).
Mizoguchi, K., Ishige, A., Aburada, M. & Tabira, T. Chronic stress attenuates glucocorticoid negative feedback: involvement of the prefrontal cortex and hippocampus.Neuroscience119, 887–897 (2003).
Reul, J. M. & de Kloet, E. R. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation.Endocrinology117, 2505–2511 (1985).A classic paper that demonstrated the existence and differential binding affinities of MRs and GRs in the brain.
Grippo, A. J., Moffitt, J. A. & Johnson, A. K. Cardiovascular alterations and autonomic imbalance in an experimental model of depression.Am. J. Physiol. Regul. Integr. Comp. Physiol.282, R1333–R1341 (2002).A demonstration of the influence of chronic stress on autonomic function in the rat.
Dhabhar, F. S., McEwen, B. S. & Spencer, R. L. Adaptation to prolonged or repeated stress–comparison between rat strains showing intrinsic differences in reactivity to acute stress.Neuroendocrinology65, 360–368 (1997).
Stamp, J. & Herbert, J. Corticosterone modulates autonomic responses and adaptation of central immediate-early gene expression to repeated restraint stress.Neuroscience107, 465–479 (2001).
Cole, M. A. et al. Selective blockade of the mineralocorticoid receptor impairs hypothalamic-pituitary-adrenal axis expression of habituation.J. Neuroendocrinol.12, 1034–1042 (2000).
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).
Fernandes, G. A. et al. Habituation and cross-sensitization of stress-induced hypothalamic-pituitary-adrenal activity: effect of lesions in the paraventricular nucleus of the thalamus or bed nuclei of the stria terminalis.J. Neuroendocrinol.14, 593–602 (2002).
Hurley, K. M., Herbert, H., Moga, M. M. & Saper, C. B. Efferent projections of the infralimbic cortex of the rat.J. Comp. Neurol.308, 249–276 (1991).
Sesack, S. R., Deutch, A. Y., Roth, R. H. & Bunney, B. S. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study withPhaseolus vulgaris leucoagglutinin.J. Comp. Neurol.290, 213–242 (1989).
Li, S. & Kirouac, G. J. Projections from the paraventricular nucleus of the thalamus to the forebrain, with special emphasis on the extended amygdala.J. Comp. Neurol.506, 263–287 (2008).
Moga, M. M., Weis, R. P. & Moore, R. Y. Efferent projections of the paraventricular thalamic nucleus in the rat.J. Comp. Neurol.359, 221–238 (1995).
Bartolomucci, A. et al. Chronic psychosocial stress persistently alters autonomic function and physical activity in mice.Physiol. Behav.80, 57–67 (2003).
Farah, V. M., Joaquim, L. F., Bernatova, I. & Morris, M. Acute and chronic stress influence blood pressure variability in mice.Physiol. Behav.83, 135–142 (2004).
LeDoux, J. The amygdala.Curr. Biol.17, R868–R874 (2007).
Bishop, S. J. Neurocognitive mechanisms of anxiety: an integrative account.Trends Cogn. Sci.11, 307–316 (2007).
Sanders, M. J., Wiltgen, B. J. & Fanselow, M. S. The place of the hippocampus in fear conditioning.Eur. J. Pharmacol.463, 217–223 (2003).
Shors, T. J. Stressful experience and learning across the lifespan.Annu. Rev. Psychol.57, 55–85 (2006).
Smotherman, W. P., Kolp, L. A., Coyle, S. & Levine, S. Hippocampal lesion effects on conditioned taste aversion and pituitary-adrenal activity in rats.Behav. Brain Res.2, 33–48 (1981).One of the first papers to show that conditioned HPA responses to an anticipated stressor (in a conditioned taste-aversion paradigm) depend on an intact hippocampus.
Sullivan, G. M. et al. Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus.Neuroscience128, 7–14 (2004).Demonstrated that the CeA is required for both contextual- and cue-conditioned HPA axis responses, whereas the BST is only necessary for contextually conditioned HPA axis responses.
Resstel, L. B., de Aguiar Correa, F. M. & Silveira Guimaraes, F. The expression of contextual fear conditioning involves activation of an NMDA receptor nitric oxide pathway in the medial prefrontal cortex.Cereb. Cortex18, 2027–2035 (2007).
Kosten, T. & Contreras, R. J. Deficits in conditioned heart rate and taste aversion in area postrema-lesioned rats.Behav. Brain Res.35, 9–21 (1989).
Supple, W. F. Jr & Leaton, R. N. Lesions of the cerebellar vermis and cerebellar hemispheres: effects on heart rate conditioning in rats.Behav. Neurosci.104, 934–947 (1990).
Furlong, T. & Carrive, P. Neurotoxic lesions centered on the perifornical hypothalamus abolish the cardiovascular and behavioral responses of conditioned fear to context but not of restraint.Brain Res.1128, 107–119 (2007).
Iwata, J., LeDoux, J. E. & Reis, D. J. Destruction of intrinsic neurons in the lateral hypothalamus disrupts the classical conditioning of autonomic but not behavioral emotional responses in the rat.Brain Res.368, 161–166 (1986).
Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?Brain Res. Brain Res. Rev.28, 309–369 (1998).
Wise, R. A. Brain reward circuitry: insights from unsensed incentives.Neuron36, 229–240 (2002).
Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory.Annu. Rev. Neurosci.29, 565–598 (2006).
Heimer, L., Zahm, D. S., Churchill, L., Kalivas, P. W. & Wohltmann, C. Specificity in the projection patterns of accumbal core and shell in the rat.Neuroscience41, 89–125 (1991).
Usuda, I., Tanaka, K. & Chiba, T. Efferent projections of the nucleus accumbens in the rat with special reference to subdivision of the nucleus: biotinylated dextran amine study.Brain Res.797, 73–93 (1998).
Goeders, N. E. Stress and cocaine addiction.J. Pharmacol. Exp. Ther.301, 785–789 (2002).
Koob, G. & Kreek, M. J. Stress, dysregulation of drug reward pathways, and the transition to drug dependence.Am. J. Psychiatry164, 1149–1159 (2007).
Cannon, W. B.Bodily changes in pain, hunger, fear and rage; an account of recent researches into the function of emotional excitement (D. Appleton and Co., New York, London, 1929).
Ulrich-Lai, Y. M. & Engeland, W. C. inHandbook of Stress and the Brain (eds Steckler, T., Kalin, N. H. & Reul, J.) 419–435 (Elsevier, Amsterdam, 2005).
Paxinos, G. & Watson, C.The Rat Brain in Stereotaxic Coordinates 4th edn (Academic, San Diego, 1998).
Acknowledgements
The authors thank present and past members of the Herman laboratory for their contributions to this work, and S. Woods for his comments on the Review. The authors' work cited in this Review was supported by US National Institutes of Health grants MH049698, MH069860, MH069725, AG12962 and DK078906.
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Authors and Affiliations
Department of Psychiatry, University of Cincinnati, Cincinnati, 45237-0506, Ohio, USA
Yvonne M. Ulrich-Lai & James P. Herman
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- James P. Herman
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Correspondence toJames P. Herman.
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Conditioning of stress responses (PDF 196 kb)
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Reward and stress effectors (PDF 286 kb)
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Glossary
- Limbic system
The collection of highly interconnected forebrain structures that are involved in processing emotion and memory.
- Chronic stress
Ongoing or repeated exposure to one or more types of stress stimuli over a period ranging from days to months.
- Preganglionic
Relating to the first neuron in the two-neuron chains that mediate autonomic responses.
- Postganglionic
Relating to the second neuron in the two-neuron chains that mediate autonomic responses.
- Subfornical organ
A forebrain circumventricular organ that lacks a blood–brain barrier.
- Preautonomic
Relating to the CNS neurons that are involved in regulating preganglionic sympathetic or parasympathetic neurons in the spinal cord and/or brainstem.
- FOS
An immediate early gene, expression of which is tightly linked to recent cellular excitation.
- Bradycardic response
A slowing of the heart rate.
- Depressor response
A decrease in blood pressure.
- Pressor response
An increase in blood pressure.
- Glutamic acid decarboxylase
(GAD). The enzyme that synthesizes GABA. It exists in two isoforms, GAD65 and GAD67.
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Ulrich-Lai, Y., Herman, J. Neural regulation of endocrine and autonomic stress responses.Nat Rev Neurosci10, 397–409 (2009). https://doi.org/10.1038/nrn2647
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