Chemogenetic modulation of CRF neurons in the BNST compensates for phenotypic behavioral differences in fear extinction learning of 5-HT2C receptor mutant mice.

Psychopharmacotherapy is often used to treat anxiety- and stress-associated psychiatric disorders, including posttraumatic stress disorder (PTSD). Adjunctive therapy is most typically used with medications that influence serotonin balance, such as selective serotonin reuptake inhibitors (SSRIs). Contrary to expectations, SSRIs show an anxiety-increasing effect during the initial treatment phase. Among the 14 different serotonin receptor subtypes, pharmacological studies have demonstrated that 5-HT2C receptors (5-HT2CRs) in the bed nucleus of the stria terminalis (BNST) play a significant role in the anxiogenic effect of acute SSRI treatment. Although numerous studies have confirmed the role of the 5-HT2CR in anxiety behavior, little is known about its involvement in learned fear and fear extinction. In particular, fear extinction is considered a central neural mechanism in the treatment of PTSD patients. Recent results from 5-HT2CR knockout mice (2CKO) revealed that global loss of 5-HT2CRs enhances fear extinction, without affecting fear acquisition. Here, we implemented a chemogenetic approach to examine the neuronal substrate which underlies this extinction-enhancing effect in 2CKO mice. DREADD-activation of BNST ^CRF neurons promotes fear extinction in 5-HT2C WT mice, whereas DREADD-inactivation of BNST ^CRF neurons impairs fear extinction in 2CKO mice. Thus, using activating and inactivating DREADDs, we were able to directionally modulate fear extinction. These findings provide a possible explanation for the fear extinction-enhancing effect in 2CKO mice with relevance for the treatment of PTSD patients.