Stress Hormones Receptors in the Amygdala Mediate the Effects of Stress on the Consolidation, but Not the Retrieval, of a Non Aversive Spatial Task

This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 µg/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive)

PRKCA Polymorphism Changes the Neural Basis of Episodic Remembering in Healthy Individuals

Everyday functioning relies on episodic memory, the conscious retrieval of past experiences, but this crucial cognitive ability declines severely with aging and disease. Vulnerability to memory decline varies across individuals however, producing differences in the time course and severity of memory problems that complicate attempts at diagnosis and treatment. Here we identify a key source of variability, by examining gene dependent changes in the neural basis of episodic remembering in healthy adults, targeting seven polymorphisms previously linked to memory. Scalp recorded Event-Related Potentials (ERPs) were measured while participants remembered words, using an item recognition task that requires discrimination between studied and unstudied stimuli. Significant differences were found as a consequence of a Single Nucleotide Polymorphism (SNP) in just one of the tested genes, PRKCA (rs8074995). Participants with the common G/G variant exhibited left parietal old/new effects, which are typically seen in word recognition studies, reflecting recollection-based remembering. During the same stage of memory retrieval participants carrying a rarer A variant exhibited an atypical pattern of brain activity, a topographically dissociable frontally-distributed old/new effect, even though behavioural performance did not differ between groups. Results replicated in a second independent sample of participants. These findings demonstrate that the PRKCA genotype is important in determining how episodic memories are retrieved, opening a new route towards understanding individual differences in memory

Blocking Mineralocorticoid Receptors prior to Retrieval Reduces Contextual Fear Memory in Mice

BACKGROUND: Corticosteroid hormones regulate appraisal and consolidation of information via mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respectively. How activation of these receptors modulates retrieval of fearful information and the subsequent expression of fear is largely unknown. We tested here whether blockade of MRs or GRs during retrieval also affects subsequent expression of fear memory. METHODOLOGY/PRINCIPAL FINDINGS: Mice were trained in contextual or tone cue fear conditioning paradigms, by pairing mild foot shocks with a particular context or tone respectively. Twenty-four hours after training, context-conditioned animals were re-exposed to the context for 3 or 30 minutes (day 2); tone-conditioned animals were placed in a different context and re-exposed to one or six tones. Twenty-four hours (day 3) and one month later, freezing behavior to the aversive context/tone was scored again. MR or GR blockade was achieved by giving spironolactone or RU486 subcutaneously one hour before retrieval on day 2. Spironolactone administered prior to brief context re-exposure reduced freezing behavior during retrieval and 24 hours later, but not one month later. Administration of spironolactone without retrieval of the context or immediately after retrieval on day 2 did not reduce freezing on day 3. Re-exposure to the context for 30 minutes on day 2 significantly reduced freezing on day 3 and one month later, but freezing was not further reduced by spironolactone. Administration of spironolactone prior to tone-cue re-exposure on day 2 did not affect freezing behavior. Treatment with RU486 prior to re-exposure did not affect context or tone-cue fear memories at any time point. CONCLUSIONS/SIGNIFICANCE: We conclude that MR blockade prior to retrieval strongly reduces the expression of contextual fear, implying that MRs, rather than GRs, play an important role in retrieval of emotional information and subsequent fear expression

A Conserved Function of C. elegans CASY-1 Calsyntenin in Associative Learning

BACKGROUND: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance. However, such studies do not allow for a functional or causal testing of newly identified candidate genes. Since polymorphisms in Calsyntenin 2 (CLSTN2) showed a significant association with episodic memory performance in humans, we tested the C. elegans CLSTN2 ortholog CASY-1 for possible functions in the associative behavior of C. elegans. METHODOLOGY/PRINCIPAL FINDINGS: Using three different associative learning paradigms and functional rescue experiments, we show that CASY-1 plays an important role during associative learning in C. elegans. Furthermore, neuronal expression of human CLSTN2 in C. elegans rescues the learning defects of casy-1 mutants. Finally, genetic interaction studies and neuron-specific expression experiments suggest that CASY-1 may regulate AMPA-like GLR-1 glutamate receptor signaling. CONCLUSION/SIGNIFICANCE: Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway

Neuroanatomical Variability of Religiosity

We hypothesized that religiosity, a set of traits variably expressed in the population, is modulated by neuroanatomical variability. We tested this idea by determining whether aspects of religiosity were predicted by variability in regional cortical volume. We performed structural magnetic resonance imaging of the brain in 40 healthy adult participants who reported different degrees and patterns of religiosity on a survey. We identified four Principal Components of religiosity by Factor Analysis of the survey items and associated them with regional cortical volumes measured by voxel-based morphometry. Experiencing an intimate relationship with God and engaging in religious behavior was associated with increased volume of R middle temporal cortex, BA 21. Experiencing fear of God was associated with decreased volume of L precuneus and L orbitofrontal cortex BA 11. A cluster of traits related with pragmatism and doubting God's existence was associated with increased volume of the R precuneus. Variability in religiosity of upbringing was not associated with variability in cortical volume of any region. Therefore, key aspects of religiosity are associated with cortical volume differences. This conclusion complements our prior functional neuroimaging findings in elucidating the proximate causes of religion in the brain

Enhanced Fear Expression in a Psychopathological Mouse Model of Trait Anxiety: Pharmacological Interventions

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias

Rejection of Unfair Offers Can Be Driven by Negative Emotions, Evidence from Modified Ultimatum Games with Anonymity

The rejection of unfair offers can be affected by both negative emotions (e.g. anger and moral disgust) and deliberate cognitive processing of behavioral consequences (e.g. concerns of maintaining social fairness and protecting personal reputation). However, whether negative emotions are sufficient to motivate this behavior is still controversial. With modified ultimatum games, a recent study (Yamagishi T, et al. (2009) Proc Natl Acad Sci USA 106∶11520–11523) found that people reject unfair offers even when this behavior increases inequity, and even when they could not communicate to the proposers. Yamagishi suggested that rejection of unfair offers could occurr without people’s concerning of maintaining social fairness, and could be driven by negative emotions. However, as anonymity was not sufficiently guaranteed in Yamagishi’s study, the rejection rates in their experiments may have been influenced by people’s concerns of protecting personal reputation (reputational concerns) in addition to negative emotions; thus, it was unclear whether the rejection was driven by negative emotions, or by reputational concerns, or both. In the present study, with specific methods to ensure anonymity, the effect of reputational concerns was successfully ruled out. We found that in a private situation in which rejection could not be driven by reputational concerns, the rejection rates of unfair offers were significantly larger than zero, and in public situations in which rejection rates could be influenced by both negative emotions and reputational concerns, rejection rates were significantly higher than that in the private situation. These results, together with Yamagishi’s findings, provided more complete evidence suggesting (a) that the rejection of unfair offers can be driven by negative emotions and (b) that deliberate cognitive processing of the consequences of the behavior can increase the rejection rate, which may benefit social cooperation

Stress Strengthens Memory of First Impressions of Others' Positive Personality Traits

Encounters with strangers bear potential for social conflict and stress, but also allow the formation of alliances. First impressions of other people play a critical role in the formation of alliances, since they provide a learned base to infer the other's future social attitude. Stress can facilitate emotional memories but it is unknown whether stress strengthens our memory for newly acquired impressions of other people's personality traits. To answer this question, we subjected 60 students (37 females, 23 males) to an impression-formation task, viewing portraits together with brief positive vs. negative behavior descriptions, followed by a 3-min cold pressor stress test or a non-stressful control procedure. The next day, novel and old portraits were paired with single trait adjectives, the old portraits with a trait adjective matching the previous day's behavior description. After a filler task, portraits were presented again and subjects were asked to recall the trait adjective. Cued recall was higher for old (previously implied) than the novel portraits' trait adjectives, indicating validity of the applied test procedures. Overall, recall rate of implied trait adjectives did not differ between the stress and the control group. However, while the control group showed a better memory performance for others' implied negative personality traits, the stress group showed enhanced recall for others' implied positive personality traits. This result indicates that post-learning stress affects consolidation of first impressions in a valence-specific manner. We propose that the stress-induced strengthening of memory of others' positive traits forms an important cue for the formation of alliances in stressful conditions

Statistical Epistasis and Functional Brain Imaging Support a Role of Voltage-Gated Potassium Channels in Human Memory

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed “missing heritability.” The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (Pnominal combined = 0.000001). The epistatic interaction was robust, as it was significant in a screening (Pnominal = 0.0000012) and in a replication sample (Pnominal = 0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (Pnominal = 0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits

Survival processing in times of stress

Recent studies have found that processing information according to an evolutionary relevant (i.e., survival) scenario improves its subsequent memorability, potentially as a result of fitness advantages gained in the ancestral past. So far, research has not revealed much about any proximate mechanisms that might underlie this so-called survival processing advantage in memory. Intriguingly, research has shown that the memorability of stressful situations is enhanced via the release of stress hormones acting on brain regions involved in memory. Since survival situations habitually involve some degree of stress, in the present study, we investigated whether stress serves as a proximate mechanism to promote survival processing. Participants rated words for their relevance to either a survival or a neutral (moving) scenario after they had been exposed to a psychosocial stressor or a no-stress control condition. Surprise retention tests immediately following the rating task revealed that survival processing and acute stress independently boosted memory performance. These results therefore suggest that stress does not serve as a proximate mechanism of the survival processing advantage in memory