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

P. Schipper,M. Hiemstra,Kari Bosch,Desirée Nieuwenhuis,Annalisa Adinolfi,Sabine Glotzbach,Bart Borghans,Dora Lopresto,G. Fernández,F. Klumpers,E. Hermans,K. Roelofs,M. Henckens,J. Homberg

Published 2019 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Reduced expression of the serotonin transporter (5-HTT) is associated with susceptibility to stress-related psychopathology, but the underlying mechanisms remain elusive. We investigated whether an aberrant physiological and neural response to threat underlies this increased vulnerability. In a cross-species approach, we investigated the association between genetically encoded differences in 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance. In both humans and rats, reduced 5-HTT expression was associated with exaggerated bradycardia or bradycardia-associated freezing, reduced activity of the medial prefrontal cortex, and increased threat-induced amygdala-periaqueductal grey connectivity and central amygdala somatostatin neuron activity. We have delineated a previously unknown neurogenetic mechanism underlying individual differences in the expression of anticipatory threat responses, contributing to stress sensitivity. 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.

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