The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response

Abstract

Background: Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and consequently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2.

Objective: Here we review the past and current state of the CRF/CRFR field, ranging from pharmacological studies to genetic mouse models and virus-mediated manipulations.

Results: Although it is well established that CRF/CRFR1 signaling mediates aversive responses, including anxiety and depression-like behaviors, a number of recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRF/CRFR1 circuits. In contrast, the UCN/CRFR2 system is less well understood and may possibly also exert divergent functions on physiology and behavior depending on the brain region, underlying circuit, and/or experienced stress conditions.

Conclusion: A plethora of available genetic tools, including conventional and conditional mouse mutants targeting CRF system components, has greatly advanced our understanding about the endogenous mechanisms underlying HPA system regulation and CRF/UCN-related neuronal circuits involved in stress-related behaviors. Yet, the detailed pathways and molecular mechanisms by which the CRF/UCN-system translates negative or positive stimuli into the final, integrated biological response are not completely understood. The utilization of future complementary methodologies, such as cell-type specific Cre-driver lines, viral and optogenetic tools will help to further dissect the function of genetically defined CRF/UCN neurocircuits in the context of adaptive and maladaptive stress responses.

Keywords: Corticotropin-releasing factor; hypothalamic-pituitary-adrenal (HPA); mouse genetic tools; neuropsychiatric disorders; stress; urocortin.

Fig. (1)

CRF regulates neuroendocrine and behavioral responses to stress. CRF integrates neuroendocrine and higher-order behavioral responses by regulating peripheral HPA axis function and modulating synaptic transmission in the CNS. ACTH: Adrenocorticotropic hormone; CRF: corticotropin-releasing factor, PVN: hypothalamic paraventricular nucleus.

Fig. (2)

Schematic illustrations of the spatial distribution and relative expression of CRF family peptides and their receptors in the mouse brain. Abbreviations: Anterior pituitary (APit), arcuate nucleus (ARC), basolateral nucleus of the amygdala (BLA), bed nucleus of the stria terminalis (BNST), caudate putamen (CPu), central nucleus of the amygdala (CeA), cerebellum (Cb), cingulate cortex (CingCx), corpus callosum (cc), cortical nucleus of the amygdala (CoA), Barrington’s nucleus (Bar), diagonal band of Broca (DBB), Edinger Westphal nucleus (EW), frontal cortex (FrCx), globus pallidus (GPe), inferior colliculi (IC), inferior olive (IO), intermediate lobe of the pituitary (IPit), locus coeruleus (LC), lateral septum (LS), laterodorsal tegmental nucleus (LDTg), lateral hypothalamic area (LHA), lateral superior olive (LSO), medial nucleus of the amygdala (MeA), medial preoptic area (MPO), medial septum (MS), medial vestibular nucleus (MV), nucleus tractus solitarii (NTS), olfactory bulb (OB), occipital cortex (OccCx), parietal cortex (ParCx), parabrachial nucleus (PB), periaquaductal gray (PAG), perifornical area (PFA), piriform cortex (Pir), pontine gray (PG), posterior pituitary (Ppit), pedunculopontine tegmental nucleus (PPTg), premammillary nucleus (PMV), paraventricular nucleus of the hypothalamus (PVN), red nucleus (R), raphe nuclei (RN), reticular thalamic nucleus (RTN), superior colliculi (SC), substantia nigra (SN), supraoptic nucleus (SON), spinal trigeminal nucleus (Sp5n), superior paraolivary nucleus (SPO), ventral medial hypothalamus (VMH), ventral tegmental area (VTA). Modified from [88].

Fig. (3)

CRF family members, their receptors and binding proteins. CRF and the UCNs signal through one of two CRF receptors (CRFR1 and CRFR2). The arrows represent ligand-receptor or ligand-binding protein interactions. Dashed arrows indicate low-affinity binding, compared to solid arrow-lines. CRF displays a relatively high affinity for CRFR1 and a low affinity for CRFR2, while UCN1 binds to both receptors with equal affinity. UCN2 and UCN3 are selective ligands for CRFR2. CRFBP and sCRFR2α are able to sequester both CRF and UCN1, while CRFBP exerts a low affinity for UCN2. Abbreviations: corticotropin-releasing factor (CRF), CRF receptor 2 (CRFR2), CRF binding protein (CRFBP), soluble variant of CRFR2 (sCRFR2α).

Fig. (4)

CRFR1 modulates anxiety-related behavior in a bidirectional manner. CRFR1 is expressed in diverse neuronal subpopulations. Selective deletion of the receptor in glutamatergic neurons reduces anxiety-related behavior while deletion in dopaminergic neurons produces the opposite effect [106].