Proposed model for development of prolonged anxiety following acute stress in CRFR2-null mice. Following acute stress in control mice (A) CRF acting at CRFR1 in the limbic forebrain produces immediate anxiety. High levels of CRF and potentially Ucn1 activate CRFR1 and more abundant CRFR2 in the DRN with a net effect to promote early firing of efferent 5-HT neurons to limbic nuclei. Activation of CRFR2 in the MRN promotes delayed 5-HT release in the mPFC at 1 to 2 h, which acts at 5-HT1AR to mediate successful coping and anxiolysis by 24 h. Negative feedback in the 5-HT system restores homeostasis by 24 h. (B) In CRFR2-null mice, the CRFR2-mediated increase in 5-HT firing cannot occur and unopposed CRFR1 activity might inhibit 5-HT neuronal firing in limbic nuclei even further. Absence of negative feedback within the 5-HT system contributes to the increased 5-HT levels observed in limbic areas at 24 h. The temporal dynamics of the 5-HT system following acute stress are dysregulated and homeostasis has not been restored. Crucially, the delayed 5-HT activity in mPFC is disrupted and successful coping has not occurred, resulting in prolonged anxiety.