Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene modulates age effects on working memory

Decline in working memory (WM) functions during aging has been associated with hippocampal dysfunction mediated by age-related changes to the corticotropin-releasing hormone (CRH) system. Recent reports suggest that GG-homozygous individuals of single nucleotide polymorphisms (rs110402 and rs242924) in the CRH receptor 1 (CRHR1) gene show increased stress vulnerability and decreased BOLD responses in WM relevant regions. However, until now, no study investigated the interaction effects of variation in the CRHR1 gene and age on individual differences in WM.Here, young, middle-aged and old subjects (N = 466) were genotyped for rs110402 and rs242924 within the CRHR1 gene and an n-back task was used to investigate the hypothesis that vulnerable genotypes (GG-homozygotes) would show impaired WM functions that might be magnified by increased CRH production with advancing age. Our results show an impact of genotype already in middle-age with significantly better performance in AT-carriers. Working memory performance in AT-carriers did not differ between young and middle-aged subjects, but was significantly impaired in old age. In GG-homozygotes, severe working memory dysfunction occurred already in middle age. Our data indicate that GG-homozygotes of CRHR1 rs110402 and rs242924 represent a genetically driven subtype of early WM impairments due to alterations in hippocampal CRHR1 activation. Early interventions that have proven effective in delaying cognitive decline appear to be particularly important for these subjects at risk for premature memory decline, who are in the prime of their personal and professional lives.     

Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits

Corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of anxiety disorders and depression. Corticotropin-releasing hormone receptor 2 (CRHR2) is one of the receptors that mediate CRH signal. The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects. As a result, significant association was observed between the polymorphism in intron 2 (rs2267717) and Openness (P = 0.004, uncorrected, anova), while no relationship was observed concerning Neuroticism. The present result suggests an association between CRHR2 and the personality trait of Openness.     

Polymorphism in CRHR1 gene affects the IL-1β levels in suicidal attempters

Approximately one million people commit suicide every year, being suicide attempts and ideation even more common. Changes in stress response and activation of the immune system have been associated with suicide risk. Here we investigated the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1β levels according to suicide ideation and attempt. This study evaluated 171 subjects of which 15 had suicidal ideation, 20 had suicide attempt and 136 were controls. Genotyping was performed by real-time PCR and IL-1β levels were measured by ELISA. Our data showed that for each point increase in IL-1β levels the risk of suicide attempt increased 5% [relative risk = 1.05 (95% CI: 1.0–1.10)]. After sample stratification by rs110402 SNP genotypes, we observed that in subjects carrying the A allele the risk raised to 15% [relative risk = 1.15 (95% CI: 1.03–1.28)], suggesting an apparent effect modification. Thus, this study showed that alterations in CRHR1 gene were associated with higher levels of IL-1β, and increased risk for suicide, reinforcing the importance of multifactorial interactions of biological markers for psychiatric disorders.     

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.     

A Single Episode of Restraint Stress Regulates Central Corticotrophin-Releasing Hormone Receptor Expression and Binding in Specific Areas of the Mouse Brain

The importance of restraining stress-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) system within tolerable limits requires efficient mechanisms for feedback inhibition. Recently, central corticotrophin-releasing hormone (CRH) receptor type 1 (CRHR1) has been shown to mediate HPA system feeback inhibition. To date, most of the data regarding stress-associated expression changes of CRHR1 and CRHR2 mRNA and their ligand CRH have been generated in rats. Taken considerable species differences into consideration, and with the growing importance of transgenic mice, a systematic analysis of the time course of expression changes of CRH and its two receptors in the mouse brain is needed to provide more insight into the regulation of the HPA system, both under physiological and pathophysiological conditions in this species. We analysed in detail the time course of expression changes of CRH, CRHR1 and CRHR2 mRNA after of restraint stress in mice in stress-relevant brain regions (paraventricular nucleus, hippocampus, neocortex). We could show a rapid, strong and long-lasting decrease in cortical and hippocampal CRHR1 mRNA expression after stress, whereas CRHR2 mRNA increased in the same neuroanatomical areas. In situ hybridisation analyses could be further confirmed at the protein level by CRH receptor autoradiography with changes in CRH binding that persisted even 7 days after a single episode of restraint stress. Our observation that stress has opposing effects on CRHR1 and CRHR2 neuronal systems supports the idea that regulation of the relative contribution of the two CRH receptors to brain CRH pathways may be essential in coordinating physiological responses to stress. We further hypothesise that the sustained alteration of CRH receptor expression and binding after a single episode of stress could mediate the long-term effects of stress on neuroendocrine function and emotional regulation.     

抑郁症患者情绪图片反应特征及杏仁核反应模式的研究

目的 探讨抑郁症患者对情感刺激的行为学反应模式及其相关的杏仁核时程反应过程.方法 12例首次发病、未经治疗的抑郁症患者(抑郁症组)和13名健康个体(健康对照组)对观看正性、中性和负性情绪图片的愉悦度等评分;并在被动注视任务下行功能磁共振成像,采用感兴趣区分析方法,比较两组杏仁核在不同情绪图片任务组块间的血氧水平依赖(BOLD)信号时间反应特征.结果 (1)抑郁症组情绪图片愉悦度评分[正性:(6.6 ±0.2)分;中性:(4.7 ±0.1)分]低于健康对照组[分别为(7.7 ±0.2)分和(5.1 ±0.1)分],负性情绪图片评分[(3.4 ±0.3)分]高于健康对照组[(2.2 ±0.2)分;P<0.01].(2)对正性情绪图片任务,两组间右侧杏仁核存在"组×时间"交互作用(P=0.002);抑郁症组杏仁核BOLD信号变化率为(0.02±0.09)%,激活时间后移至Block 2.对负性情绪图片任务,两组间左侧杏仁核有"组×时间"交互作用(P=0.008),右侧杏仁核存在组主效应(P=0.007)和时间主效应(P=0.016),抑郁症组BOLD信号变化率低于(-0.06 ±0.14)%.结论 杏仁核是抑郁症患者丧失愉悦体验和情绪低落的神经基础之一.     

Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments

Although it is well accepted that changes in the regulation of the hypothalamic-pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress-related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke.     

Differential disinhibition of the neonatal hypothalamic- pituitary-adrenal axis in brain-specific CRH receptor 1-knockout mice

In the adult, corticotropin-releasing hormone (CRH) is the key mediator for the behavioural and neuroendocrine response to stress. It has also been hypothesized that, during postnatal development of the stress system, CRH controls the activity of the HPA axis and mediates the effects of early disturbances, e.g. 24 h of maternal deprivation. In the current study we investigated the function of specific brain corticotropin-releasing hormone receptor type 1 (CRHR1) subpopulations in the control of the HPA axis during postnatal development under basal conditions as well as after 24 h of maternal deprivation. We used two conditional CRHR1-deficient mouse lines which lack this receptor, either specifically in forebrain and limbic structures (Cam-CRHR1) or in all neurons (Nes-CRHR1). Basal circulating corticosterone was increased in Nes-CRHR1 mice compared to controls. Corticosterone response to maternal deprivation was significantly increased in both CRHR1-deficient lines. In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels. In contrast, gene expression in Nes-CRHR1 pups was strikingly similar to that in maternally deprived control pups. Furthermore, maternal deprivation resulted in an enhanced response of Cam-CRHR1 pups in the brain, while expression levels in Nes-CRHR1 mouse pups were mostly unchanged. Our results demonstrate that brainstem and/or hypothalamic CRHR1 contribute to the suppression of basal corticosterone secretion in the neonate, while limbic and/or forebrain CRHR1 dampen the activation of the neonatal HPA axis induced by maternal deprivation.     

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitary-adrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wild-type or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P<0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P <0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline- and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P <0.05, 268.9% P <0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis.     

Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1

Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in early-life stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of early-life stress, and suggest that other neural circuits are also involved in the programming effects of early-life stress on anxiety-related behavior.     

抑郁症患者外显性与内隐性情绪处理的脑功能磁共振研究

目的以健康者为对照，利用脑功能磁共振研究抑郁症患者的外显性和内隐性情绪处理过程。方法2006年12月-2007年12月，收集临床诊断抑郁症患者14例（DSM-Ⅳ标准）。14例健康志愿者作为对照。采用传统的组块设计，采集患者在高兴与悲伤2组脸像刺激下，判断表情的外显性情绪处理和判断性别的内隐性情绪处理过程的脑功能磁共振图像，利用SPM2统计软件计算出个体及组内在不同表情刺激和不同任务操作下激活的脑功能区。结果①抑郁症患者判断表情时，悲伤脸像的主要激活区位于顶叶、海马旁回、基底节、梭状回、丘脑、岛叶、前扣带回及胼胝体下回；高兴脸像激活区仅有前扣带回；②抑郁症患者判断性别任务时，悲伤脸像激活区分布在额中回、顶下小叶、前扣带回、颞中回；高兴脸像未见明显脑功能激活区。结论①抑郁症患者外显性与内隐性情绪刺激的脑内加工过程不同，悲伤脸像脑功能区激活均强于高兴脸像；②与健康人群相比，不同情绪处理过程中，抑郁症患者的高兴脸像激活区较弱，而悲伤脸像的激活明显增强。提示抑郁症患者情绪处理的神经系统存在异常，对正性情绪的神经反应减弱，而对负性情绪的神经反应增强。     

Reduced negative BOLD responses in the default-mode network and increased self-focus in depression

Abstract

Objectives. Functional imaging studies in major depressive disorder (MDD) indicate abnormal resting state neural activity and negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network (DMN). Methods. Since activity in DMN regions has been associated with self-relatedness, we investigated neural activity in these regions during self-related emotional judgement and passive picture viewing in 25 patients with MDD and 25 healthy controls in an event-related fMRI design. Results. Behaviourally, MDD subjects showed significantly higher ratings of self-relatedness that also correlated with depression symptoms such as hopelessness. Neuroimaging results in MDD patients showed significantly lower negative BOLD responses (NBRs) in anterior medial cortical regions during judgement of self-relatedness while posterior medial regions showed increased NBRs. Unlike in healthy subjects, the anterior medial cortical NBRs were no longer parametrically modulated by the degree of self-relatedness in MDD patients. Conclusions. Our findings suggest that reduced NBRs in the anterior regions of the default-mode network may signify decoupling from self-relatedness in MDD patients with the consecutive abnormal increase of self-focus.     

Voltage-sensitive dye imaging demonstrates an enhancing effect of corticotropin-releasing hormone on neuronal activity propagation through the hippocampal formation

Corticotropin-releasing hormone (CRH) is thought to play an important role in the pathophysiology of stress-related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). However, knowledge about the actions of CRH at the neuronal network level is only scarce. Here, we examined whether CRH affects neuronal activity propagation through the hippocampal formation (HF), a brain region which is likely to be involved in MDD and PTSD. For this purpose, we applied voltage-sensitive dye imaging (VSDI) to specifically cut hippocampal brain slices obtained from adult mice. This approach allowed us to investigate evoked neuronal activity propagation through the HF with micrometer spatial and millisecond temporal resolution. Application of CRH (50 nM) to slices increased neuronal activity propagation from the dentate gyrus (DG) to the CA1 subfield. This effect of CRH was caused by amplification of neuronal excitation on its passage through the HF and absent in mice lacking the CRH receptor type 1 (CRHR1). In conclusion, our study presents a VSDI assay for the investigation of neuronal activity propagation through the HF and demonstrates that CRH, via CRHR1, enhances this activity propagation. This effect of CRH might contribute to alterations of memory formation seen in MDD and PTSD. Moreover, it could influence hippocampal regulation of hypothalamic-pituitary-adrenal axis (HPA-axis) activity.     

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.     

Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking

Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic-pituitary-adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1(NestinCre)) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1(NestinCre) mice as compared with control animals. Crhr1(NestinCre) mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.     

Corticotropin-releasing hormone receptor type 1 (CRHR1) genetic variation and stress interact to influence reward learning

Stress is a general risk factor for psychopathology, but the mechanisms underlying this relationship remain largely unknown. Animal studies and limited human research suggest that stress can induce anhedonic behavior. Moreover, emerging data indicate that genetic variation within the corticotropin-releasing hormone type 1 receptor gene (CRHR1) at rs12938031 may promote psychopathology, particularly in the context of stress. Using an intermediate phenotypic neurogenetics approach, we assessed how stress and CRHR1 genetic variation (rs12938031) influence reward learning, an important component of anhedonia. Psychiatrically healthy female participants (n = 75) completed a probabilistic reward learning task during stress and no-stress conditions while 128-channel event-related potentials were recorded. Fifty-six participants were also genotyped across CRHR1. Response bias, an individual's ability to modulate behavior as a function of reward, was the primary behavioral variable of interest. The feedback-related positivity (FRP) in response to reward feedback was used as a neural index of reward learning. Relative to the no-stress condition, acute stress was associated with blunted response bias as well as a smaller and delayed FRP (indicative of disrupted reward learning) and reduced anterior cingulate and orbitofrontal cortex activation to reward. Critically, rs12938031 interacted with stress to influence reward learning: both behaviorally and neurally, A homozygotes showed stress-induced reward learning abnormalities. These findings indicate that acute, uncontrollable stressors reduce participants' ability to modulate behavior as a function of reward, and that such effects are modulated by CRHR1 genotype. Homozygosity for the A allele at rs12938031 may increase risk for psychopathology via stress-induced reward learning deficits.     

Differential effect of prenatal stress on the expression of corticotrophin-releasing hormone and its receptors in the hypothalamus and amygdala in male and female rats

The present study examined the effect of prenatal stress in rats from days 13-20 of gestation on anxiogenic behaviour in the elevated plus maze (EPM) together with changes in the gene expression of corticotrophin-releasing hormone (CRH), its receptors, CRHR1 and CRHR2, as well as CRH binding protein (CRH-BP) in the paraventricular nucleus (PVN) and amygdala of their male and female offspring. Both prenatally-stressed (PS) males and females showed heightened anxiety in the EPM. Prenatal stress did not alter the gene expression of CRH or its receptors in the male PVN, although it decreased CRH-BP mRNA, which could augment the activity of free CRH. In the PVN of PS females, there was an increase in the expression of CRH, coupled with a decrease in that of CRHR2 and CRH-BP. These changes are compatible with the greater activation of the hypothalamic pituitary adrenal axis to stress in females. Anxiogenic behaviour of PS rats was associated with a reduction of CRHR2 mRNA and of CRH-BP mRNA in the amygdala of males and an increase in CRH mRNA and decrease in CRHR2 mRNA in females. Two hours after acute stress of exposure to the elevated plus maze in which heightened anxiety was manifested, increases were seen only in the amygdala of females in CRH and CRHR1 signalling, whereas CRHR2 mRNA was reduced in both sexes. The data show that both prenatal stress and acute stress in adulthood have a differential sex-dependent effect on the expression of CRH its receptors and binding protein in the PVN and amygdala of rats.     

Is there protective haplotype of dysbindin gene (DTNBP1) 3 polymorphisms for major depressive disorder

Dysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.     

Low doses of corticotropin-releasing hormone injected into the dorsal raphe nucleus block the behavioral consequences of uncontrollable stress

The behavioral consequences of uncontrollable stress that are collectively called learned helplessness (LH) are mediated in part by increased levels of serotonin (5-HT) activity in the dorsal raphe nucleus (DRN) and it's projection regions. Recently, corticotropin-releasing hormone (CRH) within the DRN has been implicated in the development of LH because intra-DRN CRH produces LH at very high doses, and because intra-DRN antagonists for the CRH 2 receptor (CRHR2) block LH. Since these behavioral effects are mediated by both 5-HT excitation and CRHR2 activation, we have suggested that CRHR2 mediates excitation of DRN 5-HT neurons. However, CRH has been shown to inhibit DRN 5-HT neurons at low doses that are expected to bind to CRHR1. Since CRHR1 antagonists were ineffective in blocking LH, we have further suggested that CRHR1 might mediate the inhibition of DRN 5-HT neurons. In support of this hypothesis, although low doses of CRH that preferentially bind CRHR1 inhibit DRN 5-HT activity, higher doses at which CRH would be expected to bind both receptor subtypes no longer inhibit DRN 5-HT. In addition, high doses of CRH are required to produce LH, which is known to be mediated by 5-HT excitation, and the CRHR2 agonist urocortin II (UCN II) produces LH at much lower doses than does CRH. The present studies show that intra-DRN CRH microinjection blocks the behavioral effects produced by DRN UCN II, but only at doses that have been shown to inhibit DRN 5-HT activity. Indeed, a higher dose of CRH that has been shown to no longer inhibit DRN 5-HT activity did not affect the behavioral consequences of DRN UCN II. In a separate experiment, the effective dose of CRH blocked the usual behavioral consequences of uncontrollable stress.     

Effects of cortisol on the memory bias for emotional words? A study in patients with depression and healthy participants using the Directed Forgetting task

Mood congruent alterations in information processing such as an impaired memory bias for emotional information and impaired inhibitory functions are prominent features of a major depressive disorder (MDD). Furthermore, in MDD patients hypothalamic–pituitary–adrenal axis dysfunctions are frequently found. Impairing effects of stress or cortisol administration on memory retrieval as well as impairing stress effects on cognitive inhibition are well documented in healthy participants. In MDD patients, no effect of acute cortisol administration on memory retrieval was found.The current study investigated the effect of acute cortisol administration on memory bias in MDD patients (N = 55) and healthy controls (N = 63) using the Directed Forgetting (DF) task with positive, negative and neutral words in a placebo controlled, double blind design. After oral administration of 10 mg hydrocortisone/placebo, the item method of the DF task was conducted. Memory performance was tested with a free recall test.Cortisol was not found to have an effect on the results of the DF task. Interestingly, there was significant impact of valence: both groups showed the highest DF score for positive words and remembered significantly more positive words that were supposed to be remembered and significantly more negative words that were supposed to be forgotten. In general, healthy participants remembered more words than the depressed patients. Still, the depressed patients were able to inhibit intentionally irrelevant information at a comparable level as the healthy controls. These results demonstrate the importance to distinguish in experimental designs between different cognitive domains such as inhibition and memory in our study.