Differences by Sex and Genotype in the Effects of Stress on Executive Functions

压力对执行功能影响的性别和基因型差异

• 批准号: 8673889
• 负责人: ADELE D DIAMOND
• 金额: $ 22.31万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673889
• 关键词: Accounting; Affect; Amygdaloid structure; Animals; Attention deficit hyperactivity disorder; Biological Factors; Brain region; Catechol O-Methyltransferase; Code; Codon Nucleotides; Cognition; Cognitive; Disadvantaged; Dopamine; Dose; Education; Educational process of instructing; Environment; Environmental Risk Factor; Enzymes; Estradiol; Estrogens; Female; Gender; Genes; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Glucocorticoid Receptor; Glutamates; Health; Hippocampus (Brain); Homozygote; Hormones; Human; Hydrocortisone; Individual; Individual Differences; Industry; Mediating; Mental Depression; Mental disorders; Methyltransferase Gene; Modeling; Neurotransmitters; Norepinephrine; Patients; Performance; Persons; Pharmaceutical Preparations; Play; Prefrontal Cortex; Primates; Problem Solving; Property; Rehabilitation therapy; Research Personnel; Rodent; Role; Schizophrenia; Self-control as a personality trait; Sex Characteristics; Short-Term Memory; Stress; Testing; Valine; Variant; Woman; Workplace; addiction; cognitive function; design; dopamine system; dopamine transporter; dosage; executive function; flexibility; genetic variant; hypothalamic-pituitary-adrenal axis; male; meetings; men; prevent; response; serotonin transporter; sex; social

DESCRIPTION (provided by applicant): The unusual properties of the prefrontal cortex (PFC) dopamine (DA) system contribute to the unusual sensitivity of PFC and the cognitive functions that depend on it to environmental and genetic variations. (Those cognitive functions are called 'executive functions' [EFs] and are important for reasoning, planning, problem-solving, and self-control.) We propose to study the effects of an environmental factor (mild stress) on EFs, testing our predictions of how and why those effects differ by biological factors (hormones and genotype). To test our hypotheses concerning the underlying mechanism, we will try to model the effects of mild stress on EFs pharmacologically. Two ways in which the DA system in PFC is unusual are: (1) It relies heavily on the catechol-O-methyltransferase (COMT) enzyme for clearing released DA (other brain regions rely heavily on the dopamine transporter). (2) Mild stress markedly increases DA in PFC (but not in other brain regions). Animal studies find a sex difference in that mild stress aids performance on cognitive tasks that require PFC in males, but hinders it in females. We propose (a) a new interpretation of that, (b) to see if this sex differene is also true in humans, and (c) to put our new interpretation to the test. We hypothesize that mild stress exerts its effect on cognition, and produces the sex difference in that, by increasing DA in PFC (rather than the mechanism being solely by increasing cortisol and affecting hippocampal functioning). If we are correct, then if we model this by pharmacologically increasing DA in PFC, we should be able to replicate the sex difference. There are two common variants of the gene that codes for the COMT enzyme, one codes for a much slower COMT enzyme than the other, clearing DA from PFC much more slowly. With a slower enzyme increasing the level of DA in PFC, the increase in PFC DA due to stress could well result in too much DA in PFC, impairing EFs. Thus we predict opposite effects of stress on cognition by COMT genotype, and we predict that by pharmacologically increasing DA in PFC, we should be able to replicate that (those homozygous for the gene coding for the faster enzyme should benefit, but those homozygous for the other version should show impaired EFs). We thus hope to put our causal model to the test by attempting to reproduce the opposing effects of mild stress in males and females and by genotype without stress but just by increasing DA in PFC. If our hypotheses are borne out, gender and genotype should be taken into account when considering the best environment and best drug dosage for aiding a person's self-control and creative problem-solving, and for minimizing a person's impulsive tendencies when trying to prevent or treat mental health disorders (such as addictions) in which EFs and the DA system in PFC are implicated and when teaching or designing a work environment.

描述（由申请人提供）：前额叶皮层（PFC）多巴胺（DA）系统的异常特性有助于PFC的异常灵敏度以及依赖于环境和遗传变异的认知函数。 （这些认知功能称为“执行功能” [EFS]，对于推理，计划，解决问题和自我控制很重要。）我们建议研究环境因素（轻度压力）对EFS的影响，对我们的EFS进行测试预测这些影响如何以及为什么因生物学因素（激素和基因型）而有所不同。为了测试有关基本机制的假设，我们将尝试对轻度应激对EFS药理的影响进行建模。 PFC中的DA系统不寻常的两种方式是：（1）它严重依赖于Catechol-O-甲基转移酶（COMT）酶以清除DA的DA（其他大脑区域很大程度上依赖多巴胺转运蛋白）。 （2）轻度压力显着增加了PFC的DA（但在其他大脑区域中没有）。动物研究发现性别差异是，轻度压力有助于男性需要PFC的认知任务的表现，但会阻碍女性。我们提出（a）对此的新解释，（b）查看这种性别在人类中是否也是正确的，（c）将我们的新解释付诸实践。我们假设轻度压力对认知产生影响，并通过增加DA来产生性别差异 PFC（而不是仅通过增加皮质醇并影响海马功能而进行的机制）。如果我们是正确的，那么如果我们通过在PFC中增加DA来对此进行建模，则应该能够复制性别差异。该基因的两个常见变体代码为COMT酶，一个代码代码比另一个酶慢得多，从PFC中清除DA的速度要慢得多。随着酶较慢增加了PFC中DA的水平，由于压力引起的PFC DA的增加可能会导致PFC中的DA过多，从而损害EFS。因此，我们预测了压力对COMT基因型认知的相反影响，并且我们预测，通过在PFC中的药理上增加DA，我们应该能够复制（纯合的基因编码更快的酶的基因应该受益，但是那些纯合为纯合酶的基因，但其他版本应显示受损的EFS）。因此，我们希望通过尝试在男性和女性中重现轻度压力的相反作用，并通过无压力的基因型来实现我们的因果模型，但仅通过增加了PFC中的DA。如果我们的假设得到了证实，则在考虑最佳环境和最佳药物剂量时应考虑性别和基因型，以帮助一个人的自我控制和创造性的解决问题，并在试图预防或治疗人的冲动倾向时最小化。在教学或设计工作环境时，EFS和DA系统涉及的心理健康障碍（例如成瘾）。