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.