Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

This corrects the article DOI: 10.1038/mp.2016.204.

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3ß phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

A common NTRK2 variant is associated with emotional arousal and brain white-matter integrity in healthy young subjects.

Dysregulation of emotional arousal is observed in many psychiatric diseases such as schizophrenia, mood and anxiety disorders. The neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) has been associated with these disorders. Here we investigated the relation between genetic variability of NTRK2 and emotional arousal in healthy young subjects in two independent samples (n1=1171; n2=707). In addition, diffusion tensor imaging (DTI) data in a subgroup of 342 participants were used to identify NTRK2-related white-matter structure differences. After correction for multiple testing, we identified a NTRK2 single nucleotide polymorphism associated with emotional arousal in both samples (n1: Pnominal=0.0003, Pcorrected=0.048; n2: Pnominal=0.0141, Pcorrected=0.036). DTI revealed significant, whole-brain corrected correlations between emotional arousal and brain white-matter mean diffusivity (MD), as well as significant, whole-brain corrected NTRK2 genotype-related differences in MD (PFWE<0.05). Our study demonstrates that genetic variability of NTRK2, a susceptibility gene for psychiatric disorders, is related to emotional arousal and-independently-to brain white-matter properties in healthy individuals.

Stress and Memory: A Selective Review on Recent Developments in the Understanding of Stress Hormone Effects on Memory and Their Clinical Relevance.

Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential.

Effects of cortisol administration on craving in heroin addicts.

Heroin dependence is a severe and chronically relapsing substance use disorder with limited treatment options. Stress is known to increase craving and drug-taking behavior, but it is not known whether the stress hormone cortisol mediates these stress effects or whether cortisol may rather reduce craving, for example, by interfering with addiction memory. The aim of the present study was to determine the effects of cortisol administration on craving in heroin-dependent patients and to determine whether the effects depend on the daily dose of heroin consumption. We used a double-blind, placebo-controlled, cross-over study in 29 heroin-dependent patients in a stable heroin-assisted treatment setting. A single oral dose of 20 mg of cortisol or placebo was administered 105 min before the daily heroin administration. The primary outcome measure was cortisol-induced change in craving. Secondary measures included anxiety, anger and withdrawal symptoms. For the visual analog scale for craving, we found a significant interaction (P = 0.0027) between study medication and heroin-dose group (that is, daily low, medium or high dose of heroin). Cortisol administration reduced craving in patients receiving a low dose of heroin (before heroin administration: P = 0.0019; after heroin administration: P = 0.0074), but not in patients receiving a medium or high dose of heroin. In a picture-rating task with drug-related pictures, cortisol administration did not affect the ratings for the picture-characteristic craving in all the three heroin-dose groups. Cortisol also did not significantly affect secondary outcome measures. In conclusion, a single administration of cortisol leads to reduced craving in low-dose heroin addicts. The present findings might have important clinical implications with regard to understanding stress effects and regarding treatment of addiction.

Substantial SNP-based heritability estimates for working memory performance.

Working memory (WM) is an important endophenotype in neuropsychiatric research and its use in genetic association studies is thought to be a promising approach to increase our understanding of psychiatric disease. As for any genetically complex trait, demonstration of sufficient heritability within the specific study context is a prerequisite for conducting genetic studies of that trait. Recently developed methods allow estimating trait heritability using sets of common genetic markers from genome-wide association study (GWAS) data in samples of unrelated individuals. Here we present single-nucleotide polymorphism (SNP)-based heritability estimates (h(2)SNP) for a WM phenotype. A Caucasian sample comprising a total of N=2298 healthy and young individuals was subjected to an N-back WM task. We calculated the genetic relationship between all individuals on the basis of genome-wide SNP data and performed restricted maximum likelihood analyses for variance component estimation to derive the h(2)SNP estimates. Heritability estimates for three 2-back derived WM performance measures based on all autosomal chromosomes ranged between 31 and 41%, indicating a substantial SNP-based heritability for WM traits. These results indicate that common genetic factors account for a prominent part of the phenotypic variation in WM performance. Hence, the application of GWAS on WM phenotypes is a valid method to identify the molecular underpinnings of WM.

The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder.

Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.

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.

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.

A genome-wide survey of human short-term memory.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.

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.

Imaging genetics of cognitive functions: Focus on episodic memory.

Human cognitive functions are highly variable across individuals and are both genetically and environmentally influenced. Recent behavioral genetics studies have identified several common genetic polymorphisms, which are related to individual differences in memory performance. In addition, imaging genetics studies are starting to explore the neural correlates of genetic differences in memory functions on the level of brain circuits. In this review we will describe how functional magnetic resonance imaging (fMRI) can be used to validate and extend findings of behavioral genetics studies of episodic memory and give examples of recent advances in this new and exciting research field. In addition, we will present advantages and problems related to the different sensitivity of behavioral- vs. imaging genetics studies and discuss possible methodological approaches for an appropriate evaluation and integration of the results. Although the field of imaging genetics of episodic memory is still young, it already became clear that imaging methods have a large potential to enhance our understanding of the neural mechanisms that underlie genetic differences in memory.

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 alpha2b-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.

Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions.

Extensive evidence from rat and human studies indicates that glucocorticoid hormones influence cognitive performance. Posttraining activation of glucocorticoid-sensitive pathways dose-dependently enhances the consolidation of long-term memory. Glucocorticoid effects on memory consolidation rely on noradrenergic activation of the basolateral amygdala and interactions of the basolateral amygdala with other brain regions. Glucocorticoids interact with the noradrenergic system both at a postsynaptic level, increasing the efficacy of the beta-adrenoceptor-cyclic AMP/protein kinase A system, as well as presynaptically in brainstem noradrenergic cell groups that project to the basolateral amygdala. In contrast, memory retrieval and working memory performance are impaired with high circulating levels of glucocorticoids. Glucocorticoid-induced impairment of these two memory functions also requires the integrity of the basolateral amygdala and the noradrenergic system. Such critical interactions between glucocorticoids and noradrenergic activation of the basolateral amygdala have important consequences for the role of emotional arousal in enabling glucocorticoid effects on these different memory functions.

Basolateral amygdala-nucleus accumbens interactions in mediating glucocorticoid enhancement of memory consolidation.

Systemic or intracerebral administration of glucocorticoids enhances memory consolidation in several tasks. Previously, we reported that these effects depend on an intact basolateral nucleus of the amygdala (BLA) and efferents from the BLA that run through the stria terminalis (ST). The BLA projects directly to the nucleus accumbens (NAc) via this ST pathway. The NAc also receives direct projections from the hippocampus and, therefore, may be a site of convergence of BLA and hippocampal influences in modulating memory consolidation. In support of this view, we found previously that lesions of either the NAc or the ST also block the memory-modulatory effect of systemically administered glucocorticoids. The present experiments examined the effects of lesions of the NAc or the ST on the memory-modulatory effects of intracerebral glucocorticoids on inhibitory avoidance training. Microinfusions of the specific glucocorticoid receptor agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362; 1.0 or 3.0 ng) into either the BLA or the hippocampus of male Sprague Dawley rats administered immediately after training enhanced the 48 hr retention performance in a dose-dependent manner. Bilateral lesions of the NAc or the ST alone did not affect retention performance but blocked the memory enhancement induced by intra-BLA or intrahippocampal glucocorticoid receptor agonist administration. These findings indicate that the BLA-NAc pathway plays an essential role in mediating glucocorticoid effects on memory consolidation and suggest that the BLA interacts with hippocampal effects on memory consolidation via this pathway.

Task-dependent effects on motor-evoked potentials and on the following silent period.

The silent period (SP) after transcranial stimulation is used as a diagnostic tool in various central nervous system disorders although no standardized experimental setup has been established. The aim of this study was to demonstrate the influence of an isotonic compared to an isometric experimental condition. The SP after transcranial magnetic brain stimulation in the biceps brachii and brachioradialis muscle was up to 130% longer when elicited during a maintain-position (isotonic) task as compared to a maintain-force task (isometric) when stimulus intensities of 5% to 25% above threshold were used. The mean SP duration in these muscles was positively correlated to the mean contraction time in both tasks. However, no such relationship was observed for the trials within the individual subjects. We speculate that the invariably longer SP of the maintain-position task was due to the different "motor set" which predictively determined the muscle behavior after the stimulus. In the maintain-position trials, the stimulus-induced long-lasting flexion movement is counteracted by a motor set aiming to relax the elbow flexors immediately after the stimulus. In the maintain-force task the contraction twitch is short and a force drop below the preset level must be prevented by a motor set aiming to contract the elbow flexors immediately after the stimulus. The latter may increase the synaptic input to the motoneuron pool and facilitate the reoccurrence of the electromyogram terminating the SP. At high-stimulus intensities the SP duration increased in both tasks, and the task-dependent differences disappeared. Therefore, when using the SP duration for diagnostic purposes, isometric conditions and high-stimulus intensities should be used.

Dependence of the transcranially induced silent period on the 'instruction set' and the individual reaction time.

OBJECTIVES AND METHODS: We looked for influences of the experimental condition on the silent period (SP) from transcranial motor cortex stimulation and analyzed how the instruction given to the subject, as well as the individual reaction time, might affect the duration of the SP in the biceps brachii muscle. RESULTS: The duration of the SP was found to critically depend on the subject's voluntary reaction of the target muscle immediately after the stimulus. With low stimulus intensity and low background force, the duration of the silent period was significantly longer in 10 of 13 subjects (P = 0.002) when they were instructed to relax quickly after the stimulus rather than to maintain the the force at a constant level. A significant shortening of the SP (P = 0.02) was observed when the subjects were instructed to perform a rapid contraction of the target muscle in reaction to the cortical stimulus. With low stimulus intensity and high background force, the same influence of the instruction set was found in 6 of 13 subjects. When the subjects were left without precise instruction, the SP duration was unpredictable. In 10 subjects, the SP corresponded to that obtained with the instruction to maintain the force at a constant level. However, in 3 subjects it was prolonged to the value observed in the 'relax' instruction. With greater stimulus intensities, the effect of the instruction set on the SP duration was generally smaller. A significant prolongation was nevertheless found at low background forces with rapid relaxation (P < 0.001), and a significant shortening was found at high background forces with rapid contraction (P < 0.001) after the stimulus. The SP duration observed with 20% of maximal voluntary contraction (MVC) significantly correlated with the individual reaction time. No such correlation was found for the SP obtained with 80% MVC. The SP was slightly longer at 20% MVC, as compared to 80% MVC within each instruction group. This effect was significant (P < 0.05) at low stimulus intensities. CONCLUSIONS: Therefore, when assessing the SP duration for diagnostic purposes, not only the stimulus intensity but also the background force and the voluntary reaction must be standardized. Furthermore, great stimulus intensities and high background forces should be used to minimise the effects of instruction set and individual reaction time.

Stress and glucocorticoids impair retrieval of long-term spatial memory.

Extensive evidence from animal and human studies indicates that stress and glucocorticoids influence cognitive function. Previous studies have focused exclusively on glucocorticoid effects on acquisition and long-term storage of newly acquired information. Here we report that stress and glucocorticoids also affect memory retrieval. We show that rats have impaired performance in a water-maze spatial task after being given footshock 30 min before retention testing but are not impaired when footshock is given 2 min or 4 h before testing. These time-dependent effects on retention performance correspond to the circulating corticosterone levels at the time of testing, which suggests that the retention impairment is directly related to increased adrenocortical function. In support of this idea, we find that suppression of corticosterone synthesis with metyrapone blocks the stress-induced retention impairment. In addition, systemic corticosterone administered to non-stressed rats 30 min before retention testing induces dose-dependent retention impairment. The impairing effects of stress and glucocorticoids on retention are not due to disruption of spatial navigation per se. Our results indicate that besides the well described effects of stress and glucocorticoids on acquisition and consolidation processes, glucocorticoids also affect memory retrieval mechanisms.