Details

Autor(en) / Beteiligte

• Schipper, Pieter
• Hiemstra, Marlies
• Bosch, Kari
• Nieuwenhuis, Desiree
• Adinolfi, Annalisa
• Glotzbach, Sabine
• Borghans, Bart
• Lopresto, Dora
• Fernández, Guillén
• Klumpers, Floris
• Hermans, Erno J.
• Roelofs, Karin
• Henckens, Marloes J. A. G.
• Homberg, Judith R.

Titel

The association between serotonin transporter availability and the neural correlates of fear bradycardia

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2019-12, Vol.116 (51), p.25941-25947

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2019

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which—similarly to the human population—mediated the 5-HTT genotype’s effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.