DISC1 gene and affective psychopathology: A combined structural and functional MRI study

The gene Disrupted-In-Schizophrenia-1 (DISC1) has been indicated as a determinant of psychopathology, including affective disorders, and shown to influence prefrontal cortex (PFC) and hippocampus functioning, regions of major interest for affective disorders. We aimed to investigate whether DISC1 differentially modulates brain function during executive and memory processing, and morphology in regions relevant for depression and anxiety disorders (affective disorders). 128 participants, with (n = 103) and without (controls; n = 25) affective disorders underwent genotyping for Ser704Cys (with Cys-allele considered as risk-allele) and structural and functional (f) Magnetic Resonance Imaging (MRI) during visuospatial planning and emotional episodic memory tasks. For both voxel-based morphometry and fMRI analyses, we investigated the effect of genotype in controls and explored genotypeXdiagnosis interactions. Results are reported at p < 0.05 FWE small volume corrected. In controls, Cys-carriers showed smaller bilateral (para)hippocampal volumes compared with Ser-homozygotes, and lower activation in the anterior cingulate cortex (ACC) and dorsolateral PFC during visuospatial planning. In anxiety patients, Cys-carriers showed larger (para)hippocampal volumes and more ACC activation during visuospatial planning. In depressive patients, no effect of genotype was observed and overall, no effect of genotype on episodic memory processing was detected. We demonstrated that Ser704Cys-genotype influences (para)hippocampal structure and functioning the dorsal PFC during executive planning, most prominently in unaffected controls. Results suggest that presence of psychopathology moderates Ser704Cys effects.     

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.     

电针对血管性认知障碍大鼠学习记忆与海马内血管内皮生长因子及其受体1、2 mRNA表达的影响

目的:探讨电针对血管性认知障碍大鼠学习记忆及海马内血管内皮生长因子(VEGF)及其受体1(VEGFR-1/Flt-1)、受体2(VEGFR-2/Flk-1)mRNA表达的影响,为临床治疗血管性认知障碍提供理论和实验依据。方法:Wistar大鼠60只,随机选取12只作为假手术组,其余大鼠采用改良的四血管阻断法进行血管性认知障碍模型复制,将模型复制成功的大鼠保留36只,随机分为模型对照组、电针治疗组和西药治疗组,每组12只。电针治疗组大鼠电针"大椎""百会""水沟""神庭"穴,西药治疗组予茴拉西坦0.0625g/kg灌胃,均1次/d,10次为1个疗程,共治疗2个疗程。采用跳台实验测试各组大鼠学习记忆成绩,测定各组大鼠的神经行为学评分,RT-PCR法检测大鼠海马VEGF、Flt-1、Flk-1mRNA的表达。结果:模型对照组大鼠学习成绩表现为反应时间延长、错误次数增多,记忆成绩表现为潜伏时间缩短、错误次数增多,神经行为学评分显著升高,海马内VEGF、Flt-1、Flk-1 mRNA表达增强,与假手术组比较差异有统计学意义(均P0.01);电针治疗组大鼠学习记忆成绩改善明显,神经行为学评分显著降低,海马内VEGF、Flt-1、Flk-1mRNA表达明显增强,与模型对照组比较,差异有统计学意义(均P0.01)。电针治疗组大鼠学习成绩、神经行为学评分、海马内VEGF mRNA及Flt-1 mRNA与西药治疗组比较差异亦有统计学意义(均P0.05)。结论:电针能显著提高血管性认知障碍大鼠学习记忆成绩,上调海马内VEGF、Flt-1、Flk-1mRNA的表达,促进了要害部位的血管生成,可能是其治疗血管性认知障碍的重要作用机制之一。     

Morphometric analysis of amygdla and hippocampus shape in impulsively aggressive and healthy control subjects

BackgroundImpulsive aggressive behavior is thought to be facilitated by activation of the limbic brain, particularly the amygdala and hippocampus., Functional imaging studies suggest abnormalities in limbic brain activity during emotional information processing in impulsively aggressive subjects with Intermittent Explosive Disorder (IED). It is not known if IED is associated with altered amygdala and hippocampus volume and shape.MethodsWe examined the volume and shape of the amygdala–hippocampal complex, using morphometric analysis of high resolution structural 3T MR scans in healthy control (HC: n = 73) subjects without history of Axis I or II psychiatric conditions and in subjects with IED (n = 67).ResultsWhile no volume differences were observed between HC and IED subjects, a significant level of morphometric deformation, suggestive of cell loss, in both amygdala and hippocampal structures was observed bilaterally in IED subjects. Analysis of a canonical variable that used the first 10 eigenvectors from both sides of the brain revealed that these morphometric deformations in the IED subjects were not due the presence of confounding variables or to comorbidities among IED subjects.ConclusionsThese data reveal that IED is associated with a significant loss of neurons in both the amygdala and hippocampus. These changes may play a role in the functional abnormalities observed in previous fMRI studies and in the pathophysiology of impulsive aggressive behavior.     

Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women

Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity.     

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P = 0.0000017, corrected P = 0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia.     

Autobiographical memory decline in Alzheimer’s disease,a theoretical and clinical overview

Autobiographical memory, or memory for personal experiences, allows individuals to define themselves and construct a meaningful life story. Decline of this ability, as observed in Alzheimer’s disease (AD), results in an impaired sense of self and identity. In our model (AMAD: Autobiographical Memory in Alzheimer’s Disease), we present a critical review of theories and findings regarding cognitive and neuroanatomical underpinnings of autobiographical memory and its decline in AD and highlight studies on its clinical rehabilitation. We propose that autobiographical recall in AD is mainly characterized by loss of associated episodic information, which leads to de-contextualization of autobiographical memories and a shift from reliving past events to a general sense of familiarity. This decline refers to retrograde, but also anterograde amnesia that affects newly acquired memories besides remote ones. One consequence of autobiographical memory decline in AD is decreased access to memories that shape self-consciousness, self-knowledge, and self-images, leading to a diminished sense of self and identity. The link between autobiographical decline and compromised sense of self in AD can also manifest itself as low correspondence and coherence between past memories and current goals and beliefs. By linking cognitive, neuroanatomical, and clinical aspects of autobiographical decline in AD, our review provides a theoretical foundation, which may lead to better rehabilitation strategies.     

表里经配穴法对脑缺血再灌注损伤大鼠海马细胞凋亡及JNK信号通路的影响

【目的】观察表里经配穴法对脑缺血再灌注损伤大鼠海马细胞凋亡及c－jun氨基末端激酶（JNK）信号通路的影响,探讨其对脑缺血再灌注损伤保护作用的可能机制。【方法】将120只SD大鼠随机分为假手术组、模型组、表里经配穴电针组、抑制剂组;参照Longa法复制局灶脑缺血再灌注模型,表里经配穴电针组取表里经配穴的足三里、三阴交和尺泽、合谷行电针治疗,每日1次。采用神经行为学评定各组大鼠不同时段神经行为, TUNEL法检测海马细胞凋亡指数,免疫组织化学法检测p－JNK表达。【结果】表里经配穴电针组、抑制剂组神经功能缺损评分均显著低于模型组（P＜0．05）;模型组凋亡指数显著高于假手术组（P＜0．01）,表里经配穴电针组和抑制剂组凋亡指数均显著低于模型组（P＜0．05）;模型组各时段p－JNK表达较假手术组显著增加（P＜0．01）,表里经配穴电针组、抑制剂组p－JNK表达较模型组显著降低（P＜0．05）。【结论】表里经配穴法可不同程度地减轻缺血再灌注后大鼠的神经功能缺损,减少细胞凋亡,其机制可能与抑制JNK信号通路有关。