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

描述（由申请人提供）：前额皮质（PFC）多巴胺（DA）系统的异常特性导致PFC及其依赖于其的认知功能对环境和遗传变异的异常敏感性。（这些认知功能被称为“执行功能”，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（轻度压力）对EFs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，我们将尝试从药理学上模拟轻度应激对EFs的影响。PFC中的DA系统不同寻常的两个方面是：(1)它严重依赖儿茶酚- o -甲基转移酶（COMT）酶来清除释放的DA（其他大脑区域严重依赖多巴胺转运蛋白）。(2)轻度应激显著增加PFC区DA（其他脑区无明显变化）。动物研究发现了性别差异，轻度压力有助于男性完成需要PFC的认知任务，但会阻碍女性完成这一任务。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)把我们的新解释付诸实践。我们假设是温和的

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.