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.

A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for time-dependent memory loss in C. elegans. Tissue-specific rescue demonstrates that MSI-1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX-2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons.

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that α-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for α-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases.

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline-and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.basolateral amygdala | norepinephrine | memory accuracy | hippocampus | systems consolidation E motionally arousing experiences are well-retained in memory (1, 2). Beyond their increased strength, emotionally enhanced memories are also often characterized by increased vividness and the subjective feeling of remembering (3, 4). Both animal and human research indicate that noradrenergic activation of the basolateral amygdala (BLA) enhances memory of emotionally arousing experiences by regulating neural plasticity and information storage processes in other brain regions (5-12). A majority of studies investigating the effects of noradrenergic activation of the BLA in memory have focused on episodic (declarative) or contextual tasks that involve functioning of the hippocampus (13-17). The BLA sends extensive projections to the hippocampus (18) and has a major impact on hippocampal functioning (19-21).There is extensive evidence that the memory enhancement induced by BLA activation by norepinephrine (NE) administration or emotional arousal during or shortly after learning involves hippocampal activation (20,(22)(23)(24). This activa...

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.emotion | trauma | single nucleotide polymorphism E motional experiences are typically well remembered, but there is a large, partly genetically controlled, variability for this phenomenon (1). On the one hand, enhanced memory for emotionally arousing events can be seen as an adaptive mechanism, which helps us to remember important information (2). On the other hand, strong memory of an extremely aversive event may contribute to the development and symptoms of posttraumatic stress disorder (PTSD) (3-6). In a previous study we reported that a deletion variant of the ADRA2B gene was significantly associated with emotional memory in healthy humans and with traumatic memory in a traumatized population, but not significantly with the risk for PTSD (1). Thus, so far, there is no evidence indicating that genetic factors that predispose individuals to build strong aversive memories could also be risk factors for PTSD.Considerable evidence suggests that protein kinases, in particular protein kinase A (PKA), protein kinase C (PKC), Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and mitogenactivated protein kinase (MAPK), play an important role in the formation of emotional memory in animals (7,8). To study whether the genes encoding these protein kinases are also related with human emotional memory, we applied a behavioral genetics approach and captured the variability of these genes with 2,005 singlenucleotide polymorphisms (SNPs) (Methods and SI Appendix).The 2,005 selected SNPs were analyzed in an initial sample of 723 young healthy Swiss adults (476 females, 247 males; median age, 22 y; range, 18-35 y), who underwent memory testing. Subjects were presented 24 neutral, 24 positive, and 24 negative photographs in a random order. The photographs were taken from the international affective picture system (IAPS) (9) and presented for 2.5 s each. Immediately following the presentation of each photograph, subjects were asked to rate it for valence and arousal using the IAPS rating scales. After a delay of 10 min, during which subjects performe...