Is it really a matter of simple dualism? Corticotropin-releasing factor receptors in body and mental health.

Donny Janssen,Tamás Kozicz

doi:10.3389/fendo.2013.00028

Abstract

Physiological responses to stress coordinated by the hypothalamo-pituitary-adrenal axis are concerned with maintaining homeostasis in the presence of real or perceived challenges. Regulators of this axis are corticotrophin releasing factor (CRF) and CRF related neuropeptides, including urocortins 1, 2, and 3. They mediate their actions by binding to CRF receptors (CRFR) 1 and 2, which are located in several stress-related brain regions. The prevailing theory has been that the initiation of and the recovery from an elicited stress response is coordinated by two elements, viz. the (mainly) opposing, but well balanced actions of CRFR1 and CRFR2. Such a dualistic view suggests that CRF/CRFR1 controls the initiation of, and urocortins/CRFR2 mediate the recovery from stress to maintain body and mental health. Consequently, failed adaptation to stress can lead to neuropathology, including anxiety and depression. Recent literature, however, challenges such dualistic and complementary actions of CRFR1 and CRFR2, and suggests that stress recruits CRF system components in a brain area and neuron specific manner to promote adaptation as conditions dictate.

Highlights

The concept of stress and adaptation was first observed in 1936 and further defined in 1951 (Selye, 1936, 1951)
THAT CHALLENGE THE DUALISTIC ACTION OF CRFR1 AND CRFR2 IN STRESS (MAL)ADAPTATION Conditional mutagenesis of CRFR1 using a Cre-Lox system has led to the development of various conditional knockouts were CRFR1 has been deleted in specific neuron populations previously implicated in stress and stress-associated anxiety and depression: (a) CRFR1GLU-CKO, where CRFR1 is deleted in forebrain glutamatergic neurons; (b) CRFR1GABA-CKO, deleting the receptor in forebrain GABAergic neurons; (c) CRFR1DA-CKO, carrying CRFR1 deletion in midbrain dopaminergic neurons; and (d) CRFR15HT-CKO, deleting CRFR1 in brainstem serotonergic neurons (Refojo et al, 2011) (Figure 2)
CRFR1GLU-CKO mice showed reduced anxiety-like behavior pointing toward a central role of glutamate neurotransmission in stress induced anxiety

Summary

Introduction

The concept of stress and adaptation was first observed in 1936 and further defined in 1951 (Selye, 1936, 1951). First shown to be important regulators of the endocrine stress response, the CRF family of neuropeptides is known to play a role in diverse roles of homeostatic balance, important in mobilization of resources and behaviors during stress (Bale and Vale, 2004). Members of the CRF peptide family play a role in regulation of food intake and satiety, as well as gastrointestinal tract motility, vascular tone, and development, and acoustic and cardiac function (Heinrichs et al, 1992; Spina et al, 1996; Parkes et al, 1997; Okosi et al, 1998; Koob and Heinrichs, 1999; Maillot et al, 2000; Terui et al, 2001; Vetter et al, 2002; Inoue et al, 2003)

Methods

Results

Conclusion