Corticotropin Releasing Hormone, Receptor Regulation and the Stress Response

doi:10.1016/S1043-2760(98)00079-4

Trends in Endocrinology & Metabolism

Volume 9, Issue 8, 1 October 1998, Pages 329-336

https://doi.org/10.1016/S1043-2760(98)00079-4 Get rights and content

Abstract

Corticotropin releasing hormone (CRH) coordinates behavioral, autonomic and hormonal responses to stress, including activation of the hypothalamic–pituitary–adrenal (HPA) axis with stimulation of adrenocorticotropin (ACTH) and glucocorticoids. Differential changes of expression of CRH and vasopressin(VP) in the parvicellular hypothalamic paraventricular nucleus (PVN), as well as regulation of CRH and VP receptors, are critical for the responsiveness of the HPA axis during stress. Pituitary CRH receptor (CRH-R)expression and content is controlled by the coordinated action of CRH, VP and glucocorticoids. Marked changes in hypothalamic and pituitary CRH-R expression support a key regulatory role for CRH in the HPA axis and the integrated stress response.

Section snippets

Stress and the Hypothalamic CRH System

The major site of CRH production is the hypothalamic PVN, which consists of three major subdivisions (Fig. 2): (1) anterior and medial-dorsal parvicellular CRH neurons with axons projecting to hypophyseal portal capillaries in the external zone of the median eminence; (2) dorsolateral magnocellular vasopressinergic and oxytocinergic neurons projecting to the posterior pituitary through the internal zone of the median eminence—these neurons also express small amounts of CRH and their activity

Effects of CRH

In humans and rats, CRH is the major regulator of corticotroph function, with actions on ACTH secretion, proopiomelanocortin (POMC) transcription and cell mitosis (Vale et al., 1983, Levin and Roberts, 1991, Childs et al., 1995). These effects of CRH are mediated by adenylate cyclase/cAMP/protein kinase A-dependent mechanisms triggered by binding of CRH to CRH-R1 in the corticotroph (Abou-Samra et al., 1987). Activation of Ca²⁺ channels secondary to increases in cAMP contributes to the full

Conclusions

CRH produced in the PVN and other areas of the brain acts upon receptors in the anterior pituitary and limbic system to coordinate behavioral, autonomic and endocrine responses to stress. The main hormonal response is stimulation of the HPA axis, which involves CRH and VP secretion from parvicellular neurons of the PVN, with consequent stimulation of pituitary ACTH secretion and adrenal glucocorticoids. Repeated stimuli are associated either with desensitization or maintained ACTH responses to

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To ensure the unrestricted expression of maternal behaviour peripartum, activity of the corticotropin-releasing factor (CRF) system needs to be minimised. CRF binding protein (CRF-BP) might be crucial for this adaptation, as its primary function is to sequester freely available CRF and urocortin1, thereby dampening CRF receptor (CRF-R) signalling. So far, the role of CRF-BP in the maternal brain has barely been studied, and a potential role in curtailing activation of the stress axis is unknown.
We studied gene expression for CRF-BP and both CRF-R within the paraventricular nucleus (PVN) of the hypothalamus. In lactating rats, Crh-bp expression in the parvocellular PVN was significantly higher and Crh-r1 expression in the PVN significantly lower compared to virgin rats. Acute CRF-BP inhibition in the PVN with infusion of CRF(6–33) increased basal plasma corticosterone concentrations under unstressed conditions in dams. Furthermore, while acute intra-PVN infusion of CRF increased corticosterone secretion in virgin rats, it was ineffective in vehicle (VEH)-pre-treated lactating rats, probably due to a buffering effect of CRF-BP. Indeed, pre-treatment with CRF(6–33) reinstated a corticosterone response to CRF in lactating rats, highlighting the critical role of CRF-BP in maintaining attenuated stress reactivity in lactation. To our knowledge, this is the first study linking hypothalamic CRF-BP activity to hypothalamic-pituitary-adrenal axis regulation in lactation. In terms of behaviour, acute CRF-BP inhibition in the PVN under non-stress conditions reduced blanket nursing 60 min and licking/grooming 90 min after infusion compared to VEH-treated rats, while increasing maternal aggression towards an intruder. Lastly, chronic intra-PVN inhibition of CRF-BP strongly reduced maternal aggression, with modest effects on maternal motivation and care.
Taken together, intact activity of the CRF-BP in the PVN during the postpartum period is essential for the dampened responsiveness of the stress axis, as well as for the full expression of appropriate maternal behaviour.
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An individual's social environment can have widespread effects on their physiology, including effects on oxidative stress and hormone levels. Many studies have suggested that variation in oxidative stress experienced by individuals of different social statuses might be due to endocrine differences, however, few studies have evaluated this hypothesis. Here, we assessed whether a suite of markers associated with oxidative stress in different tissues (blood/plasma, liver, and gonads) had social status-specific relationships with circulating testosterone or cortisol levels in males of a cichlid fish, Astatotilapia burtoni. Across all fish, blood DNA damage (a global marker of oxidative stress) and gonadal synthesis of reactive oxygen species [as indicated by NADPH-oxidase (NOX) activity] were lower when testosterone was high. However, high DNA damage in both the blood and gonads was associated with high cortisol in subordinates, but low cortisol in dominants. Additionally, high cortisol was associated with greater production of reactive oxygen species (greater NOX activity) in both the gonads (dominants only) and liver (dominants and subordinates). In general, high testosterone was associated with lower oxidative stress across both social statuses, whereas high cortisol was associated with lower oxidative stress in dominants and higher oxidative stress in subordinates. Taken together, our results show that differences in the social environment can lead to contrasting relationships between hormones and oxidative stress.
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Release of corticotropin-releasing hormone (CRH) from CRH neurons activates the hypothalamo–pituitary–adrenal (HPA) axis, one of the main physiological stress response systems. Complex feedback loops operate in the HPA axis and understanding the neurobiological mechanisms regulating CRH neurons is of great importance in the context of stress disorders. In this article, we review how in vivo studies in zebrafish have advanced knowledge of the neurobiology of CRH neurons. Disrupted-in-schizophrenia 1 (DISC1) mutant zebrafish have blunted stress responses and can be used to model human stress disorders. We propose that DISC1 influences the development and functioning of CRH neurons as a mechanism linking DISC1 to psychiatric disorders.
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Trends in Endocrinology & Metabolism

Corticotropin Releasing Hormone, Receptor Regulation and the Stress Response

Abstract

Section snippets

Stress and the Hypothalamic CRH System

Effects of CRH

Conclusions

Front Neuroendocrinol

Front Neuroendocrinol

Front Neuroendocrinol

Mol Cell Endocrinol

Front Neuroendocrinol

J Biol Chem

Trends Neurosci

Brain Res

Brain Res Mol Brain Res

J Biol Chem

Recent Prog Horm Res

Front Neuroendocrinol

Prog Neurobiol

Biphasic inhibition of adrenocortico-tropin release by corticosterone in cultured anterior pituitary cells

Endocrinology

Mechanisms of action of CRF and other regulators of ACTH release in pituitary corticotrophs

Ann New York Acad Sci

Differential regulation of hypothalamic pituitary corticotropin releasing hormone receptors during development of adjuvant-induced arthritis in the rat

J Endocrinol

Corticotropin releasing factor receptors: distribution and regulation in brain, pituitary and peripheral tissues

Ann New York Acad Sci

Endotoxin decreases corticotropin-releasing factor receptor 1 messenger ribonucleic acid levels in the rat pituitary

Endocrinology

Stress-induced increase in vasopressin and corticotropin releasing factor expression in hypophysiotropic paraventricular neurons

Endocrinology

Glucocorticoids inhibit corticotropin-releasing factors induced production of adenosine 3′,5′-monophosphate in cultured anterior pituitary cells

Endocrinology

Corticotropin releasing factor: effects on the autonomic nervous system and visceral systems

Fed Proc

Expression cloning of a human corticotropin releasing factor receptor

Proc Natl Acad Sci U S A

Activation of protein kinase C and L calcium channels enhances binding of biotinylated corticotropin releasing hormone by anterior pituitary corticotrophs

Mol Endocrinol

Cytochemical studies of CRH receptors in anterior lobe corticotrophs: binding, glucocorticoid regulation and endocytosis of [biotinyl-Ser1]CRF

Endocrinology

Corticotropin releasing hormone and epidermal growth factor: mitogens for anterior pituitary corticotropes

Endocrinology

Corticotrope response to removal of releasing factors and corticosteroids in vivo

Endocrinology

Stress, feedback and facilitation in the hypothalamus pituitary adrenal axis

J Neuroendocrinol

Repeated stress-induced activation of corticotropin-releasing factor neurons enhances vasopressin stores and colocalization with corticotropin-releasing factor in the median eminence of rats

Neuroendocrinology

Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin

Nature

Differential regulation of brain and pituitary corticotropin-releasing factor receptors by corticosterone

Endocrinology

Rapid regulation of corticotropin-releasing hormone gene transcription in vivo

Mol Endocrinol

Glucocorticoid regulation of corticotropin releasing factor 1 receptor expression in pituitary derived AtT-20 cells

Mol Pharmacol

Cytochemical studies of CRH receptors in anterior lobe corticotrophs: binding, glucocorticoid regulation and endocytosis of [biotinyl-Ser¹]CRF