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.     

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.     

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。     

耐药性颞叶内侧癫痫发作前期海马脑电特征分析

目的 观察耐药性颞叶内侧癫痫患者发作前期海马电极脑电活动特点,为判断和切除癫痫病灶提供神经电生理学依据.方法 对16例非侵入性手段难以明确病灶的耐药性颞叶内侧癫痫患者进行双侧海马电极监测,患者停用抗癫痫药在非麻醉状态下监测48～72 h,分析癫痫发作前期海马电极脑电图资料,探讨耐药性颞叶内侧癫痫发作前期海马电极脑电活动特点.结果 16例发作间期记录到背景活动基础上出现局限于某几个电极点的阵发性高幅慢波1例、发作性快波节律1例、棘波或棘尖慢复合波14例,视为异常脑电活动;经过48～ 72 h监测,10例监测到33次临床癫痫发作,发作起始期海马电极均可记录到清晰可辨的癫痫样脑电波形.结论 颞叶内侧癫痫临床发作起始期海马电极癫痫样放电清晰可辨,部位局限,易于确定癫痫性活动起源部位.对于非侵入性手段难以判断癫痫样放电起源的颞叶内侧癫痫可采用脑立体定向技术植入海马深部电极进行脑电监测.     

Hippocampal neuronal degeneration in the traumatic brain injury mouse: non-trivial effect of scalp incision

Objectives: In experimental models of traumatic brain injury (TBI), posttraumatic hippocampal neuronal degeneration in the cornu ammonis 1 (CA1), and/or the cornu ammonis 3 (CA3) regions are regarded as the most notable phenotypic appearances relating to the pathophysiology of human post-concussion syndrome. However, these morphological changes are often also seen in subjects without TBI, namely ‘sham’ groups. The frequencies and reasons of appearance of hippocampal neuronal degeneration in mice with TBI and/or sham are not clear.

Methods: We compared the frequencies of hippocampal neuronal degeneration among three groups: TBI (mice with external force impact performed by Marmarou’s weight drop model after scalp incision), sham (mice with scalp incision alone), and control (mice with neither external force impact nor scalp incision), using hematoxylin and eosin stain in day 6 (n = 5 in each group.) Isoflurane was used for anesthesia in all mice.

Results: The frequencies were 80, 100, and 20% in CA1, and 20, 40, and 60% in CA3, for TBI, sham, and control, respectively. In CA1, a significant difference of the frequency was observed between sham and control (p = 0.048), but not, between TBI and sham (p = 1.000) in Fisher’s exact test. In CA3, no significant difference in the frequency was observed between the three groups.

Conclusion: Scalp incision, rather than external impact force, might affect the CA1 hippocampal neuronal degeneration in mice with TBI. In addition, factor(s) other than external impact force or scalp incision may also cause hippocampal neuronal degeneration in both CA1 and CA3. Careful interpretation is needed concerning hippocampal neuronal degeneration induced by a weight drop device observed in mice with TBI.     

电针对血管性痴呆大鼠海马胆碱能神经的影响

目的　研究电针对血管性痴呆大鼠海马胆碱能神经的影响。方法　将 48只Wistar大白鼠随机分为 4组 :假手术对照组、模型组、电针治疗组、模型非治疗组 ,每组 12只。采用反复夹闭双侧颈总动脉再灌注法制作血管性痴呆大鼠模型 ,应用避暗法、胆碱酯酶组织化学染色法观察电针对大鼠的记忆功能及海马胆碱能神经的影响。结果　电针治疗组中有记忆力的大鼠占 5 4.5 5 % ,模型非治疗组为 9.0 9% ,电针治疗组明显高于模型非治疗组 (P <0 .0 1) ;电针治疗组的海马胆碱酯酶阳性纤维的密度亦明显高于模型非治疗组(P <0 .0 1)。结论　电针对血管性痴呆大鼠有显著的治疗作用 ,其机制可能与增加海马胆碱能神经的密度有关。     

Lasting effects of stress physiology on the brain: Cortisol reactivity during preschool predicts hippocampal functional connectivity at school age

Prolonged exposure to glucocorticoid stress hormones, such as cortisol in humans, has been associated with structural and functional changes in the hippocampus. The majority of research demonstrating these associations in humans has been conducted in adult, clinical, or severely maltreated populations, with little research investigating these effects in young or more typically developing populations. The present study sought to address this gap by investigating longitudinal associations between preschool (3−5 years) and concurrent (5–9 years) cortisol reactivity to a laboratory stressor and hippocampal functional connectivity during a passive viewing fMRI scan. Results showed that, after controlling for concurrent cortisol reactivity, greater total cortisol release in response to a stressor during preschool predicted increased anterior and posterior hippocampal connectivity with the precuneus and cingulate gyrus at school-age. These findings are consistent with literature from adult and non-human investigations and suggest lasting impacts of early stress physiology on the brain.