Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
Serotonin Deficiency Increases Context-Dependent Fear Learning Through Modulation of Hippocampal Activity
Waider Jonas, Popp Sandy, Mlinar Boris, Montalbano Alberto, Bonfiglio Francesco, Aboagye Benjamin, Thuy Elisabeth, Kern Raphael, Thiel Christopher, Araragi Naozumi, Svirin Evgeniy, Schmitt-Böhrer Angelika G., Corradetti Renato, Lowry Christopher A., Lesch Klaus-Peter
Frontiers in Neuroscience