The association between serotonin transporter availability and the neural correlates of fear bradycardia
Number of pages
SourceProceedings of the National Academy of Sciences USA, 116, 51, (2019), pp. 25941-25947
Article / Letter to editor
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PI Group Memory and Emotion
SW OZ BSI KLP
PI Group Affective Neuroscience
Proceedings of the National Academy of Sciences USA
Subject130 000 Cognitive Neurology & Memory; 230 Affective Neuroscience; Experimental Psychopathology and Treatment; Radboudumc 13: Stress-related disorders DCMN: Donders Center for Medical Neuroscience
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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