5-HT2C RECEPTOR MODULATION OF LEARNED AND INNATE FEAR: SEROTONERGIC CONTROL OF FEAR EXTINCTION AND PREDATOR THREAT COPING

Dysregulation of serotonergic signaling is a hallmark of anxiety- and stress-related psychiatric disorders, including post-traumatic stress disorder (PTSD). Previous studies have highlighted the involvement of the serotonin 2C receptor (5-HT2CR) in anxiety modulation and in the paradoxical anxiogenic effects observed during early selective serotonin reuptake inhibitor (SSRI) treatment. However, its role in learned fear extinction and innate threat processing remains unclear. Previous studies report that global deletion of 5-HT2CRs enhances fear extinction without affecting fear acquisition. Here, we show that in male mice, chemogenetic DREADD-mediated bidirectional modulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (BNST) reveals a critical role of BNST^CRF neurons in fear extinction learning. Specifically, activation of these neurons facilitates extinction in wild-type mice, whereas their inhibition impairs extinction in knockout mice, offering a mechanistic explanation for the observed extinction-supporting 5-HT2C knockout. In an innate fear paradigm, exposure to the predator odor 2-methyl-2-thiazoline (2MT) reveals genotype-dependent differences in coping strategies, with male 5-HT2C knockout mice exhibiting a threat-intensity–dependent shift toward increased passive coping behavior under high-threat conditions. cFos analysis following high-threat exposure revealed genotype- and sex-specific activation patterns in anterior dorsal and oval BNST (BNSTad, BNSTov) subregions, male-specific effects in the medial (MHb) and lateral habenula (LHb), and genotype-dependent changes in the laterodorsal tegmentum (LDT). These findings indicate that 5-HT2CR-dependent BNST circuits coordinate fear extinction in learned fear and innate predator threat responses, with sex- and genotype-specific effects emerging in complex threat contexts relevant for anxiety disorders.