Abstract
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.
Highlights
Anxiety disorders are common and result in substantial economic costs to individuals and society (Bereza et al, 2009)
Previous studies of lifelong deficiency of brain 5-HT synthesis are consistent with the hypothesis that the brain serotonergic system plays an important role in control of anxiety-like behaviors (Mosienko et al, 2015), fear learning, and behavioral responses to stress (Gutknecht et al, 2015), effects that might be due to alterations in GABAergic transmission (Jorgensen et al, 2013; Waider et al, 2013)
We previously showed that tryptophan hydroxylase 2 (Tph2) mutant (Tph2−/−) mice display enhanced acquisition of conditioned fear and escape-oriented behavior in response to aversive foot shock, in association with altered basolateral amygdala function (Waider et al, 2017)
Summary
Anxiety disorders are common and result in substantial economic costs to individuals and society (Bereza et al, 2009). Evidence suggests that serotonin plays an important role in control of anxiety and fear responses (Lesch et al, 1996; Lowry et al, 2005; Maier and Watkins, 2005; Maier et al, 2006; Baratta et al, 2016; Bocchio et al, 2016). Previous studies of lifelong deficiency of brain 5-HT synthesis are consistent with the hypothesis that the brain serotonergic system plays an important role in control of anxiety-like behaviors (Mosienko et al, 2015), fear learning, and behavioral responses to stress (Gutknecht et al, 2015), effects that might be due to alterations in GABAergic transmission (Jorgensen et al, 2013; Waider et al, 2013). Of particular interest to contextual fear conditioning is the dorsal hippocampus (dHip; Bauer, 2015), which receives serotonergic projections primarily from the median raphe nucleus (Azmitia and Whitaker-Azmitia, 1995; McQuade and Sharp, 1997; Lowry, 2002)
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