Klara Spalek

A genetic variation of the noradrenergic system is related to differential amygdala activation during encoding of emotional memories

Emotionally arousing events are typically well remembered, but there is a large interindividual variability for this phenomenon. We have recently shown that a functional deletion variant of ADRA2B, the gene encoding the α2b-adrenergic receptor, is related to enhanced emotional memory in healthy humans and enhanced traumatic memory in war victims. Here, we investigated the neural mechanisms of this effect in healthy participants by using fMRI. Carriers of the ADRA2B deletion variant exhibited increased activation of the amygdala during encoding of photographs with negative emotional valence compared with noncarriers of the deletion. Additionally, functional connectivity between amygdala and insula was significantly stronger in deletion carriers. The present findings indicate that the ADRA2B deletion variant is related to increased responsivity and connectivity of brain regions implicated in emotional memory.

Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation–which was associated with lower NR3C1 expression–was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

Aversive stimuli lead to differential amygdala activation and connectivity patterns depending on catechol-O-methyltransferase Val158Met genotype

The functional Val158Met polymorphism in the gene coding for the catechol-O-methyltransferase (COMT), the major enzyme degrading the catecholaminergic neurotransmitters dopamine, norepinephrine, and epinephrine, has been associated with differential reactivity in limbic and prefrontal brain areas in response to aversive stimuli. However, studies on COMT-genotype effects on activity of the amygdala, a brain region centrally involved in affective processing, have yielded inconsistent results. Here we investigated the impact of the COMT Val158Met polymorphism on amygdala activity and connectivity during processing of emotional and neutral pictures using functional magnetic resonance imaging (fMRI) in 56 healthy participants. Homozygosity for the low-activity Met allele was positively correlated with increased activation in the right amygdala in response to unpleasant, but not pleasant pictures. In addition, the Met allele exerted an additive effect on the positive connectivity between the right amygdala and orbitofrontal regions. Our results support previous reports of a COMT-genotype-dependent difference in amygdala responsivity as well as connectivity, and highlight the importance of naturally occurring genetic variations in the catecholaminergic system for neural activity underlying affective processing.

CPEB3 is associated with human episodic memory

Cytoplasmic polyadenylation element-binding (CPEB) proteins are crucial for synaptic plasticity and memory in model organisms. A highly conserved, mammalian-specific short intronic sequence within CPEB3 has been identified as a ribozyme with self-cleavage properties. In humans, the ribozyme sequence is polymorphic and harbors a single nucleotide polymorphism that influences cleavage activity of the ribozyme. Here we show that this variation is related to performance in an episodic memory task and that the effect of the variation depends on the emotional valence of the presented material. Our data suggest a role for human CPEB3 in human episodic memory.

Testosterone levels in healthy men are related to amygdala reactivity and memory performance

Testosterone is a steroid hormone thought to influence both emotional and cognitive functions. It is unknown, however, if testosterone also affects the interaction between these two domains, such as the emotional arousal-induced enhancement of memory. Healthy subjects (N=234) encoded pictures taken from the International Affective Picture System (IAPS) during functional magnetic resonance imaging (fMRI) and underwent a free recall test 10 min after memory encoding. We show that higher endogenous testosterone levels at encoding were associated with higher arousal ratings of neutral pictures in men. fMRI analysis revealed that higher testosterone levels were related to increased brain activation in the amygdala during encoding of neutral pictures. Moreover, endogenous testosterone levels were positively correlated with the number of freely recalled neutral pictures. No such relations were found in women. These findings point to a male-specific role for testosterone in enhancing memory by increasing the biological salience of incoming information.

Dynamic modulation of amygdala-hippocampal connectivity by emotional arousal

Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence.

A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene.

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10−8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory.

The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: A joint meta-analysis of published and new data

BACKGROUND The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functionally relevant single nucleotide polymorphism (SNP). The gene itself, as well as the SNP rs6265, have been implicated in hippocampal learning and memory. However, imaging genetic studies have produced controversial results about the impact of this SNP on hippocampal volumes in healthy subjects. METHODS We examined the association between the rs6265 polymorphism and hippocampal volume in 643 healthy young subjects using automatic segmentation and subsequently included these data in a meta-analysis based on published studies with 5298 healthy subjects in total. RESULTS We found no significant association between SNP rs6265 and hippocampal volumes in our sample (g=0.05, p=0.58). The meta-analysis revealed a small, albeit significant difference in hippocampal volumes between genotype groups, such that Met-carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (g=0.09, p=0.04), an association that was only evident when manual (g=0.22, p=0.01) but not automatic tracing approaches (g=0.04, p=0.38) were used. Studies using manual tracing showed evidence for publication bias and a significant decrease in effect size over the years with increasing sample sizes. CONCLUSIONS This study does not support the association between SNP rs6265 and hippocampal volume in healthy individuals. The weakly significant effect observed in the meta-analysis is mainly driven by studies with small sample sizes. In contrast, our original data and the meta-analysis of automatically segmented hippocampal volumes, which was based on studies with large samples sizes, revealed no significant genotype effect. Thus, meta-analyses of the association between rs6265 and hippocampal volumes should consider possible biases related to measuring technique and sample size.

Continuous Theta Burst Stimulation over the Left Dorsolateral Prefrontal Cortex Decreases Medium Load Working Memory Performance in Healthy Humans

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load.