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The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.
The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.
Background:
Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans.
Methods:
An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265.
Results:
The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation.
Conclusions:
Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans.