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

TL;DR

This study shows that manipulating specific neurons in the brain can improve fear extinction learning in mice lacking serotonin 5-HT2C receptors, which may help treat PTSD.

Contribution

The study identifies BNSTCRF neurons as a key substrate for fear extinction enhancement in 5-HT2C receptor mutant mice using chemogenetics.

Findings

DREADD activation of BNSTCRF neurons improves fear extinction in wild-type mice.

DREADD inactivation of BNSTCRF neurons impairs fear extinction in 5-HT2C receptor knockout mice.

Bidirectional modulation of BNSTCRF neurons explains enhanced fear extinction in 5-HT2C receptor mutants.

Abstract

Psychopharmacotherapy is often used to treat anxiety- and stress-associated psychiatric disorders, including post-traumatic 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 BNSTCRF neurons promotes fear extinction in 5-HT2CR WT mice, whereas DREADD-inactivation of BNSTCRF neurons impairs fear extinction in 2CKO mice. Thus, using activating and inactivating DREADDs, we were able to bidirectionally 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.

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