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: 8835089
• 负责人: ADELE D DIAMOND
• 金额: $ 22.13万
• 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/8835089
• 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; addiction; causal model; cognitive function; cognitive task; collaborative environment; design; dopamine system; dopamine transporter; dosage; executive function; flexibility; genetic variant; hypothalamic-pituitary-adrenal axis; male; meetings; men; prevent; response; serotonin transporter; sex; social; stress reactivity

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）系统的不寻常特性导致PFC和认知功能对环境和遗传变异的不寻常敏感性。（这些认知功能被称为“执行功能”[EF]，对推理，计划，解决问题和自我控制很重要。我们建议研究环境因素（轻度应激）对EF的影响，测试我们对生物因素（激素和基因型）如何以及为什么这些影响不同的预测。为了验证我们关于潜在机制的假设，我们将尝试模拟轻度应激对EFs的影响。PFC中的DA系统有两个不寻常之处：（1）它严重依赖于儿茶酚-O-甲基转移酶（COMT）来清除释放的DA（其他大脑区域严重依赖于多巴胺转运蛋白）。(2)轻度应激显著增加PFC中的DA（但不在其他脑区）。动物研究发现，在需要PFC的认知任务中，轻度压力有助于男性的表现，但会阻碍女性的表现。我们提出（a）一个新的解释，（B）看看这种性别差异是否也适用于人类，（c）把我们的新解释进行测试。我们假设轻微的 应激对认知功能产生影响，并产生性别差异，应激可通过增加脑内DA含量， PFC（而不是仅仅通过增加皮质醇和影响海马功能的机制）。如果我们是正确的，那么如果我们通过增加PFC中的DA来模拟这一点，我们应该能够复制性别差异。编码COMT酶的基因有两种常见变体，一种编码的COMT酶比另一种慢得多，从PFC中清除DA的速度要慢得多。随着较慢的酶增加PFC中的DA水平，由于压力导致PFC DA的增加很可能导致PFC中过多的DA，从而损害EF。因此，我们通过COMT基因型预测了应激对认知的相反影响，并且我们预测，通过快速增加PFC中的DA，我们应该能够复制这种情况（那些编码更快酶的基因的纯合子应该受益，但那些编码另一种酶的纯合子应该表现出受损的EF）。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影响，并通过基因型在没有压力的情况下，只是通过增加PFC中的DA，来测试我们的因果模型。如果我们的假设得到证实，那么在考虑最佳环境和最佳药物剂量以帮助一个人的自我控制和创造性解决问题时，应该考虑性别和基因型，以及当试图预防或治疗涉及EF和PFC中的DA系统的心理健康障碍（例如成瘾）时以及当教学或设计工作环境时，用于最小化人的冲动倾向。